Abstrac neurobiologia dei DSA (da selezionare)

Primary Cilia as a Possible Link between Left-Right Asymmetry and Neurodevelopmental Diseases

Andrey Trulioff 1,†, Alexander Ermakov 1,2 and Yegor Malashichev

Abstract: Cilia have multiple functions in the development of the entire organism, and participate in the development and functioning of the central nervous system. In the last decade, studies have shown that they are implicated in the development of the visceral left-right asymmetry in different vertebrates. At the same time, some neuropsychiatric disorders, such as schizophrenia, autism, bipolar disorder, and dyslexia, are known to be associated with lateralization failure. In this review, we consider possible links in the mechanisms of determination of visceral asymmetry and brain lateralization, through cilia. We review the functions of seven genes associated with both cilia, and with neurodevelopmental diseases, keeping in mind their possible role in the establishment of the left-right brain asymmetry.

Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs

Kristiina Tammimies,*,†,1 Andrea Bieder,*,1 Gilbert Lauter,*,1 Debora Sugiaman-Trapman,* Rachel Torchet,* Marie-Estelle Hokkanen,‡ Jan Burghoorn,* Eero Castre ́n,‡ Juha Kere,*,§,{ Isabel Tapia-Pa ́ez,*,2

and Peter Swoboda*,3

*Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; †Center of Neurodevelopmental Disorders (KIND), Pediatric Neuropsychiatry Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; ‡Neuroscience Center and §Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland; and {Folkha ̈lsan Institute of Genetics, Helsinki, Finland

ABSTRACT: DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of these DCGs by Regulatory Factor X transcription factors (RFX TFs), a gene family known for transcriptionally regulating ciliary genes. We identify conserved X-box motifs in the promoter regions of DYX1C1, DCDC2, and KIAA0319 and dem- onstrate their functionality, as well as the ability to recruit RFX TFs using reporter gene and electrophoretic mobility shift assays. Furthermore, we uncover a complex regulation pattern between RFX1, RFX2, and RFX3 and their significant effect on modifying the endogenous expression of DYX1C1 and DCDC2 in a human retinal pigmented epithelial cell line immortalized with hTERT (hTERT-RPE1). In addition, induction of ciliogenesis increases the expression of RFX TFs and DCGs. At the protein level, we show that endogenous DYX1C1 localizes to the base of the cilium, whereas DCDC2 localizes along the entire axoneme of the cilium, thereby validating earlier localization studies using overexpression models. Our results corroborate the emerging role of DCGs in ciliary function and characterize functional noncoding elements, X-box promoter motifs, in DCG promoter regions, which thus can be targeted for mutation screening in dyslexia and ciliopathies associated with these genes.

REVIEW

Citation: Transl Psychiatry (2017) 7, e987; doi:10.1038/tp.2016.240 www.nature.com/tp

Neurogenetics of developmental dyslexia: from genes to

behavior through brain neuroimaging and cognitive and

sensorial mechanisms

S Mascheretti1,5, A De Luca2,3,5, V Trezzi1, D Peruzzo2, A Nordio2,3, C Marino1,4 and F Arrigoni2

Developmental dyslexia (DD) is a complex neurodevelopmental deficit characterized by impaired reading acquisition, in spite
of adequate neurological and sensorial conditions, educational opportunities and normal intelligence. Despite the successful characterization of DD-susceptibility genes, we are far from understanding the molecular etiological pathways underlying the development of reading (dis)ability. By focusing mainly on clinical phenotypes, the molecular genetics approach has yielded mixed results. More optimally reduced measures of functioning, that is, intermediate phenotypes (IPs), represent a target for researching disease-associated genetic variants and for elucidating the underlying mechanisms. Imaging data provide a viable IP for complex neurobehavioral disorders and have been extensively used to investigate both morphological, structural and functional brain abnormalities in DD. Performing joint genetic and neuroimaging studies in humans is an emerging strategy to link DD-candidate genes to the brain structure and function. A limited number of studies has already pursued the imaging–genetics integration in DD. However, the results are still not sufficient to unravel the complexity of the reading circuit due to heterogeneous study design and data processing. Here, we propose an interdisciplinary, multilevel, imaging–genetic approach to disentangle the pathways from genes to behavior. As the presence of putative functional genetic variants has been provided and as genetic associations with specific cognitive/sensorial mechanisms have been reported, new hypothesis-driven imaging–genetic studies must gain momentum. This approach would lead to the optimization of diagnostic criteria and to the early identification of ‘biologically at-risk’ children, supporting the definition of adequate and well-timed prevention strategies and the implementation of novel, specific

remediation approach.

Translational Psychiatry (2017) 7, e987; doi:10.1038/tp.2016.240; published online 3 January 2017

From DEPARTMENT OF BIOSCIENCES AND NUTRITION Karolinska Institutet, Stockholm, Sweden

REGULATION AND FUNCTION OF CILIARY DYSLEXIA CANDIDATE GENES

Andrea Bieder

Dyslexia is defined as an unexpected difficulty in reading despite normal intelligence, senses and instruction. It is the most common learning disability with estimated 5-10% of the population affected. Its heredity is estimated to about 40-60%. Despite the established heredity of the condition, it has been very challenging to pinpoint the underlying genes. In the past 15 years, a number of dyslexia candidate genes have been suggested. A handful of them have been replicated in several studies, including DYX1C1, DCDC2 and KIAA0319. More recently, the very same genes have been independently associated to functions of the cilium. Cilia are microtubule-based organelles present on the surface of most eukaryotic cells.

The aim of this thesis was to investigate the molecular functions of ciliary dyslexia candidate genes and their role at the cilium.

In paper I, we found X-box motifs in the promoter regions of DYX1C1, DCDC2 and KIAA0319 and showed that they are functional and able to bind ciliogenic RFX transcription factors. Knockdown of certain RFX transcription factors altered the expression of DYX1C1 and DCDC2, but not KIAA0319. Overall, we strengthened the evidence for DYX1C1 and DCDC2 as ciliary genes.

In paper II, we identified DCDC2 as a causative gene for nephronophthisis-related ciliopathy (NPHP-RC) with loss-of function mutations present in two affected families. We observed localization of DCDC2 to the ciliary axoneme of affected organs and demonstrated a crucial role of the Wnt pathway in the pathogenesis of NPHP-RC. 3D modeling in spheroids and in vivo modeling in zebrafish confirmed these observations.

In paper III, we identified CPAP as an interacting partner of both DYX1C1 and DCDC2. In addition, we observed genetic pathway synergy between DYX1C1 and DCDC2 using zebrafish and a human ciliated cell model.
In paper IV, we performed transcriptomics on differentiating human neuroepithelial stem cells and characterized the expression of dyslexia candidate genes. We found that some dyslexia candidate genes are upregulated during human neuronal differentiation. Remarkably, we identified the group of ciliary genes as the major group of upregulated genes. In addition, we showed that cilia are present on the surface of neuronal cells throughout differentiation.

In paper V, we asked whether dyslexia and ciliopathies might have a common genetic origin by investigating the genome of two individuals with situs inversus and dyslexia. We identified rare variants in dynein heavy chain genes likely causing their situs inversus phenotype. Their involvement in dyslexia remains to be determined.

In conclusion, the work conducted within this thesis strengthened and expanded on the role of DYX1C1 and DCDC2 at the cilium and in ciliopathies and identified the group of ciliary genes as a major gene class in human neuronal differentiation. A link between cilia and dyslexia remains elusive.

Knockdown of Dyslexia-Gene Dcdc2 Interferes with Speech Sound Discrimination in Continuous Streams

Tracy Michelle Centanni,1,2 Anne B. Booker,3 Fuyi Chen,3 X
Robert L. Rennaker,1 Joseph J. LoTurco,3 and Michael P. Kilgard1
1University of Texas at Dallas, Richardson, Texas 75080, 2Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and 3University of Connecticut, Storrs, Connecticut 06269

Dyslexia is the most common developmental language disorder and is marked by deficits in reading and phonological awareness. One theory of dyslexia suggests that the phonological awareness deficit is due to abnormal auditory processing of speech sounds. Variants in DCDC2 and several other neural migration genes are associated with dyslexia and may contribute to auditory processing deficits. In the current study, we tested the hypothesis that RNAi suppression of Dcdc2 in rats causes abnormal cortical responses to sound and impaired speech sound discrimination. In the current study, rats were subjected in utero to RNA interference targeting of the gene Dcdc2 or a scrambled sequence. Primary auditory cortex (A1) responses were acquired from 11 rats (5 with Dcdc2 RNAi; DC􏰀) before any behavioral training. A separate group of 8 rats (3 DC􏰀) were trained on a variety of speech sound discrimination tasks, and auditory cortex responses were acquired following training. Dcdc2 RNAi nearly eliminated the ability of rats to identify specific speech sounds from a continuous train of speech sounds but did not impair performance during discrimination of isolated speech sounds. The neural responses to speech sounds in A1 were not degraded as a function of presentation rate before training. These results suggest that A1 is not directly involved in the impaired speech discrimination caused by Dcdc2 RNAi. This result contrasts earlier results using Kiaa0319 RNAi and suggests that different dyslexia genes may cause different deficits in the speech processing circuitry, which may explain differential responses to therapy.

Key words: access; candidate gene; cortex; perception; reading; representation

Significance Statement

Although dyslexia is diagnosed through reading difficulty, there is a great deal of variation in the phenotypes of these individuals. The underlying neural and genetic mechanisms causing these differences are still widely debated. In the current study, we demonstrate that suppression of a candidate-dyslexia gene causes deficits on tasks of rapid stimulus processing. These animals also exhibited abnormal neural plasticity after training, which may be a mechanism for why some children with dyslexia do not respond to intervention. These results are in stark contrast to our previous work with a different candidate gene, which caused a different set of deficits. Our results shed some light on possible neural and genetic mechanisms causing heterogeneity in the dyslexic population.

Increased Expression of the Dyslexia Candidate Gene DCDC2 Affects Length and Signaling of Primary Cilia in Neurons

Satu Massinen1., Marie-Estelle Hokkanen2., Hans Matsson3, Kristiina Tammimies3, Isabel Tapia-Pa ́ez3, Vanina Dahlstro ̈m-Heuser2, Juha Kuja-Panula2, Jan Burghoorn3,4, Kristian E. Jeppsson3,4, Peter Swoboda3,4, Myriam Peyrard-Janvid3, Rune Toftga ̊rd3, Eero Castre ́n2*, Juha Kere1,2,3,5

1 Research Program’s Unit, Molecular Medicine and Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 2 Neuroscience Center, University of Helsinki, Helsinki, Finland, 3 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden, 4 School of Life Sciences, So ̈ derto ̈ rn University College, Huddinge, Sweden, 5Folkha ̈lsan Institute of Genetics, Helsinki, Finland

Abstract

DCDC2 is one of the cadidate susceptibility genes for dyslexia. It belongs to the superfamily of doublecortin domain containing proteins that bind to microtubules, and it has been shown to be involved in neuronal migration. We show that the Dcdc2 protein localizes to the primary cilium in primary rat hippocampal neurons and that it can be found within close proximity to the ciliary kinesin-2 subunit Kif3a. Overexpression of DCDC2 increases ciliary length and activates Shh signaling, whereas downregulation of Dcdc2 expression enhances Wnt signaling, consistent with a functional role in ciliary signaling. Moreover, DCDC2 overexpression in C. elegans causes an abnormal neuronal phenotype that can only be seen in ciliated neurons. Together our results suggest a potential role for DCDC2 in the structure and function of primary cilia.

Methodology article

Open Access

Comparison of slow and fast neocortical neuron migration using a new in vitro model
Anna J Nichols1, Laurel H Carney2,3 and Eric C Olson*1

Address: 1Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY 13210, USA, 2Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA and 3Department of Neurobiology & Anatomy, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA

Published: 5 June 2008 Received: 19 December 2007

BMC Neuroscience 2008, 9:50 doi:10.1186/1471-2202-9-50
This article is available from: http://www.biomedcentral.com/1471-2202/9/50

Abstract

Background: Mutations, toxic insults and radiation exposure are known to slow or arrest the migration of cortical neurons, in most cases by unknown mechanisms. The movement of migrating neurons is saltatory, reflecting the intermittent movement of the nucleus (nucleokinesis) within the confines of the plasma membrane. Each nucleokinetic movement is analogous to a step. Thus, average migration speed could be reduced by lowering step frequency and/or step distance.

Results: To assess the kinetic features of cortical neuron migration we developed a cell culture system that supports fiber-guided migration. In this system, the majority of fiber-apposed cells were neurons, expressed age-appropriate cortical-layer specific markers and migrated during a 30 min imaging period. Comparison of the slowest and fastest quartiles of cells revealed a 5-fold difference in average speed. The major determinant of average speed in slower cells (6–26 μm/hr) was step frequency, while step distance was the critical determinant of average speed in faster cells (>26 μm/ hr). Surprisingly, step distance was largely determined by the average duration of the step, rather than the speed of nucleokinesis during the step, which differed by only 1.3-fold between the slowest and fastest quartiles.

Conclusion: Saltatory event frequency and duration, not nucleokinetic speed, are the major determinants of average migration speed in healthy neurons. Alteration of either saltatory event frequency or duration should be considered along with nucleokinetic abnormalities as possible contributors to pathological conditions.

The Influence of Dyslexia Candidate Genes on Reading Skill in Old Age

Michelle Luciano1,2 · Alan J. Gow1,3 · Alison Pattie1,2 · Timothy C. Bates1,2 · Ian J. Deary1,2

Received: 23 February 2018 / Accepted: 23 June 2018 / Published online: 29 June 2018 © The Author(s) 2018

Abstract

A number of candidate genes for reading and language impairment have been replicated, primarily in samples of children with developmental disability or delay, although these genes are also supported in adolescent population samples. The present study used a systematic approach to test 14 of these candidate genes for association with reading assessed in late adulthood (two cohorts with mean ages of 70 and 79 years). Gene-sets (14 candidates, axon-guidance and neuron migration pathways) and individual SNPs within each gene of interest were tested for association using imputed data referenced to the 1000 genomes European panel. Using the results from the genome-wide association (GWA) meta-analysis of the two cohorts (N = 1217), a competitive gene-set analysis showed that the candidate gene-set was associated with the reading index (p = .016) at a family wise error rate corrected significance level. Neither axon guidance nor neuron migration pathways were significant. Whereas individual SNP associations within CYP19A1, DYX1C1, CNTNAP2 and DIP2A genes (p < .05) did not reach corrected significance their allelic effects were in the same direction as past available reports. These results suggest that reading skill in normal adults shares the same genetic substrate as reading in adolescents, and clinically disordered reading, and highlights the utility of adult samples to increase sample sizes in the genetic study of developmental disorders.

FASEB J. 2008 Aug; 22(8): 3001–3009.

doi: 10.1096/fj.07-104455

PMCID: PMC2493457

PMID: 18445785

The complex of TFII-I, PARP1, and SFPQ proteins regulates the DYX1C1 gene implicated in neuronal migration and dyslexia

Isabel Tapia-Páez,* Kristiina Tammimies,* Satu Massinen,† Ananda L. Roy,‡ and Juha Kere*†,1

three genes DYX1C1, DCDC2, and KIAA0319; TFII-I, SFPQ, and PARP1. This finding supports the concept that these pairs of proteins might have coregulatory roles on target genes.

Funzioni

PARP è stata trovata nel nucleo cellulare, il suo ruolo principale è quello di individuare e segnalare le rotture a singolo filamento del DNA (SSB) all’apparato enzimatico coinvolto nella riparazione degli SSB. L’attivazione di PARP consiste di un’immediata risposta cellulare a danni metabolici, chimici e indotti da radiazioni ai singoli filamenti di DNA. Quando PARP individua un SSB si lega al DNA, e , dopo cambi strutturali, inizia la sintesi di catene di poli ADP-ribosio (PAR) che fungono da segnale per altri enzimi di riparazione del DNA come la DNA ligase III (LigIII), DNA polimerasi beta (polβ) e proteine scaffold(di sostegno) come la XRCC1. Dopo la riparazione , le catene PAR sono degradate dalla PARG(Poli ADP-ribosio glicoidrolase).[1]

Inoltre, NAD+ è necessario come substrato per generare i monomeri di ADP-ribosio. L’iperattivazione della PARP può esaurire le riserve di NAD+ cellulare e indurre un progressivo esaurimento di ATP, dal momento che l’ossidazione del glucosio è inibita, e morte cellulare per necrosi. A questo proposito, PARP è inattivata (scissa) dalla caspasi-3 (in un dominio specifico dell’enzima) durante l’apoptosi.

Gli enzimi PARP sono essenziali in diversi tipi di funzione cellulare[2] , inclusa l’espressione dei geni dell’infiammazione[3]: PARP1 è necessaria per indurre la l’espressione del gene ICAM-1 da parte delle cellule muscolari lisce, in risposta al TNF[4]. Ruolo nelle mutazioni Epigenetiche

Le modificazioni post trascrizionali mediate da PARP di proteine come CTCF possono influenzare la quantità di metilazioni nei dinucleotidi CpG. È stato proposto che PARP possa influenzare la quantità del DNA metilato tramite legame diretto con la DNA metiltransferasi(DNMT-1) dopo il legame con le catene di ADP-ribosio e l’interazione con CTCF.

Inattivazione di PARP

PARP viene inattivata tramite una caspasi. Si ritiene che avvenga un’inattivazione spontanea in presenza di vasti danni del DNA. In questi casi, per la riparazione dei Danni ci vorrebbe più energia di quella disponibile, quindi questa energia viene recuperata per le altre cellule del tessuto tramite l’apoptosi.

Polymorphisms in DCDC2 and S100B associate

with developmental dyslexia

Hans Matsson1, Mikael Huss2,3, Helena Persson1, Elisabet Einarsdottir1, Ettore Tiraboschi1,

Jaana Nopola-Hemmi4, Johannes Schumacher5, Nina Neuhoff6, Andreas Warnke7, Heikki Lyytinen8,

Gert Schulte-Körne6, Markus M Nöthen9, Paavo HT Leppänen10, Myriam Peyrard-Janvid1 and

Juha Kere1,2,11,12

Genetic studies of complex traits have b

S100 calcium-binding protein B (S100B) is a protein of the S-100 protein family.

S100 proteins are localized in the cytoplasm and nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 21q22.3. Function

S100B is glial-specific and is expressed primarily by astrocytes, but not all astrocytes express S100B. It has been shown that S100B is only expressed by a subtype of mature astrocytes that ensheath blood vessels and by NG2-expressing cells.[5]

This protein may function in neurite extension, proliferation of melanoma cells, stimulation of Ca2+ fluxes, inhibition of PKC-mediated phosphorylation, astrocytosis and axonal proliferation, and inhibition of microtubule assembly. In the developing CNS it acts as a neurotrophic factor and neuronal survival protein. In the adult organism it is usually elevated due to nervous system damage, which makes it a potential clinical marker.

Clinical significance

Chromosomal rearrangements and altered expression of this gene have been implicated in several neurological, neoplastic, and other types of diseases, including Alzheimer’s disease, Down’s syndrome, epilepsy, amyotrophic lateral sclerosis, schwannoma, melanoma, and type I diabetes.[6]

It has been suggested that the regulation of S100B by melittin has potential for the treatment of epilepsy.[7]

From DEPARTMENT OF BIOSCIENCES AND NUTRITION

Karolinska Institutet, Stockholm, Sweden

REGULATION AND FUNCTION OF

CILIARY DYSLEXIA CANDIDATE GENES

Andrea Bieder 2018

ABSTRACT

Dyslexia is defined as an unexpected difficulty in reading despite normal intelligence, senses

and instruction. It is the most common learning disability with estimated 5-10% of the

population affected. Its heredity is estimated to about 40-60%. Despite the established

heredity of the condition, it has been very challenging to pinpoint the underlying genes. In the

past 15 years, a number of dyslexia candidate genes have been suggested. A handful of them

have been replicated in several studies, including DYX1C1, DCDC2 and KIAA0319. More

recently, the very same genes have been independently associated to functions of the cilium.

Cilia are microtubule-based organelles present on the surface of most eukaryotic cells.

The aim of this thesis was to investigate the molecular functions of ciliary dyslexia candidate

genes and their role at the cilium.

In paper I, we found X-box motifs in the promoter regions of DYX1C1, DCDC2 and

KIAA0319 and showed that they are functional and able to bind ciliogenic RFX transcription

factors. Knockdown of certain RFX transcription factors altered the expression of DYX1C1

and DCDC2, but not KIAA0319. Overall, we strengthened the evidence for DYX1C1 and

DCDC2 as ciliary genes.

In paper II, we identified DCDC2 as a causative gene for nephronophthisis-related

ciliopathy (NPHP-RC) with loss-of function mutations present in two affected families. We

observed localization of DCDC2 to the ciliary axoneme of affected organs and demonstrated

a crucial role of the Wnt pathway in the pathogenesis of NPHP-RC. 3D modeling in

spheroids and in vivo modeling in zebrafish confirmed these observations.

In paper III, we identified CPAP as an interacting partner of both DYX1C1 and DCDC2. In

addition, we observed genetic pathway synergy between DYX1C1 and DCDC2 using

zebrafish and a human ciliated cell model.

In paper IV, we performed transcriptomics on differentiating human neuroepithelial stem

cells and characterized the expression of dyslexia candidate genes. We found that some

dyslexia candidate genes are upregulated during human neuronal differentiation. Remarkably,

we identified the group of ciliary genes as the major group of upregulated genes. In addition,

we showed that cilia are present on the surface of neuronal cells throughout differentiation.

In paper V, we asked whether dyslexia and ciliopathies might have a common genetic origin

by investigating the genome of two individuals with situs inversus and dyslexia. We

identified rare variants in dynein heavy chain genes likely causing their situs inversus

phenotype. Their involvement in dyslexia remains to be determined.

In conclusion, the work conducted within this thesis strengthened and expanded on the role of

DYX1C1 and DCDC2 at the cilium and in ciliopathies and identified the group of ciliary

genes as a major gene class in human neuronal differentiation. A link between cilia and

dyslexia remains elusive.

Cilia in Brain Development and Disease

ByGilbert Lauter, Peter Swoboda, Isabel Tapia-Páez

Ciliopathies comprise a group of human disorders associated with genetic mutations that alter cilia structure and function. We describe a few well-established ciliopathies with associated neurological phenotypes. As an example for a human brain condition with a more tenuous connection to cilia we present dyslexia, or reading disorder.

The development of the vertebrate brain follows a tightly coordinated course of partially concomitant events. Progressive regionalization of larger brain areas into defined progenitor fields depends on the locally restricted action of specific gene sets involved in patterning. Within discrete progenitor fields further dynamic morphogenetic processes ensure proper maturation through controlled cell proliferation, differentiation and migration. Proper cell placement is crucial for subsequent neuronal wiring, which leads to functional connectivity and neuronal circuits, and there by ensures proper brain function.

Cilia are microtubule-based cell protrusions encased by a specialized membrane. Depending on cell type cilia serve as signaling centers or function in (cell) motility. In their function as specialized signaling compartments cilia are involved in the reception and transduction of multiple signals from the environment of a cell. Cilia are abundantly present in many different regions of the vertebrate brain. The importance of cilia function can be found throughout all and at all levels of brain morphogenetic processes. We focus on the role of cilia in the predominant SHH signaling pathway and give an overview of its impact on various cilia-associated and -dependent brain patterning events. We then discuss and summarize the functions of cilia in subsequent morphogenetic processes like stem cell niche proliferation, cell migration and neuronal wiring, as well as the role of cilia during later stages of brain development andin the adult brain.

Ciliopathies comprise a group of human disorders associated with genetic mutations that alter cilia structure and function. We describe a few well-established ciliopathies with associated neurological phenotypes. As an example for a human brain condition with a more tenuous connection to cilia we present dyslexia, or reading disorder.

dyslexia candidate gene DYX1C1 is essential for cilia growth and function

g with heterogeneous phenotypes & genotypes

Both at the genetic [76,77] and behavioral [78] levels phenotypes appear to be heterogeneous

and may also, in some cases, reflect atypical neurodevelopmental variation during neural

migration [79,80] rather than normal genetic variation [4]. The Human Gene Nomenclature

Committee defined nine genomic loci for dyslexia, DYX1–9 [76]. Four loci for dyslexia gene

candidates have been hypothesized to be involved in regulating neural migration [77]:

▪ DYX1C1 (also EKN1) on chromosome 15

▪ R0B01 on chromosome 3

▪ KIAA0319 on chromosome 6

DCDC2, also on chromosome 6

The dyslexia-associated gene Dcdc2 is required for spike-timing

precision in mouse neocortex

Alicia Che, Matthew J. Girgenti, and Joseph LoTurco

Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269

Abstract

Background—Variants in dyslexia-associated genes, including DCDC2, have been linked to

altered neocortical activation, suggesting that dyslexia associated genes may play as of yet

unspecified roles in neuronal physiology.

Methods—Whole-cell patch clamp recordings were used to compare the electrophysiological

properties of regular spiking (RS) pyramidal neurons of neocortex in Dcdc2 knock out (KO) and

wild-type (WT) mice. RNA-seq and RT-PCR were performed to identify and characterize changes

in gene expression in Dcdc2 KOs.

Results—Neurons in KOs showed increased excitability and decreased temporal precision in

action potential (AP) firing. The RNA-seq screen revealed that the N-methyl-D-aspartate receptor

(NMDAR) subunit Grin2B was elevated in Dcdc2 KOs, and an electrophysiological assessment

confirmed a functional increase in spontaneous NMDAR-mediated activity. Remarkably, the

decreased AP temporal precision could be restored in mutants by treatment with either the

NMDAR antagonist APV or the NMDAR 2B subunit (NR2B)-specific antagonist Ro 25-6981.

Conclusions—These results link the function of the dyslexia-associated gene Dcdc2 to spike

timing through activity of NMDAR.

In this study we sought to determine whether the genetic loss of Dcdc2 is associated with

measureable cellular neurophysiological changes in pyramidal neurons of mouse neocortex.

In the initial characterization we focused on properties of AP rate and AP timing, and found

consistently heightened excitability and altered spike-time precision in pyramidal neurons in

KOs. High throughput RNA-sequencing of the WT and KOs revealed up-regulation of the

2B subunit of NMDAR, Grin2B, and blocking NMDARs restored measures of temporal

precision in KO neurons to WT levels. Our results indicate that Dcdc2 functions in

maintaining temporal coding in neocortical neurons by regulating the expression and

function of NMDARs in neocortical pyramidal neurons. Our study indicates

the possible link between a dyslexia-associated gene, Dcdc2, and a cellular physiological

dysfunction in spike-time precision that could be the basis for changes in temporal

processing on a system level.

Dcdc2 is one of the 11-member doublecortin (DCX) gene family, whose molecular

functions are mostly inferred from the DCX domain and its ability to bind microtubules

(53). Although Dcdc2 biochemically interacts with tubulin and JIP 1/2 (54), its molecular

role remains elusive. Members of DCX families have been shown to be involved in neuronal

migration, intracellular transport, and cell signaling through protein-protein interaction (55).

Given the specific increase in NMDAR-mediated activity and Grin2B expression in Dcdc2

KO mice, it is possible that Dcdc2 is involved in homeostatic Grin2B transcript up regulation. The mRNA up-regulation of Grin2B in KOs also suggests the possibility that

Dcdc2 acts as a co-repressor or RNA binding protein that destabilizes Grin2B, regulating

Grin2B transcript levels directly. In fact, some members of the DCX-family can localize to

the nucleus and Dcdc2 itself has a domain consistent with possible nuclear localization.

Future studies will test these hypotheses by investigating interactions between Dcdc2 and

known proteins involved in the transport of NR2B protein or Grin2B transcript, cellular

localization of Dcdc2, and potential link between Dcdc2 and regulatory regions on Grin2B.

Our study demonstrates that a genetic manipulation of a dyslexia-associated gene leads to

increases in NMDAR activity. Several possibilities may account for this elevated activity: 1)

an increased number of postsynaptic NMDARs; 2) an increased number of synapses; 3)

increased ambient glutamate concentration; 4) an increased number of presynaptic

NMDARs [comprised of mostly NR1/NR2B in the cortex after early postnatal stages (56–

58)], which leads to higher transmitter release probability from the presynaptic terminals.

Elevated Grin2B mRNA expression level and potential functional changes associated with

this increase (such as altered NMDAR subunit composition, change in receptor distribution,

or change in developmental switch) does not directly provide evidence for favoring one of

the above listed possibilities. Therefore, considering the dynamic regulation of NMDARs

and its subunits, further work needs to be done to identify the specific cause of increased

NMDAR activity, particularly in relation to elevated Grin2B expression level.

It is interesting to note that short-term memory for words in individuals with RD has been

found to link to variants in GRIN2B (59) GRIN2B – glutamate ionotropic receptor NMDA type subunit 2B

. NMDAR activation is well known for its positive

role in synaptic plasticity and learning. Intriguingly, increased NMDAR activity would be

predicted to enhance plasticity at synapses by Hebbian mechanisms, but at the same time

decreased spike-timing precision would tend to decrease Hebbian plasticity in a network.

This balance may be a homeostatic change to counter spurious spike-timing dependent

plasticity in networks that could result from elevated NMDAR activity. Alternatively, a

network with greater synaptic plasticity but with increased spike-time variability may be

more dynamic in terms of new patterns that can be stored

Meta-analysis of the Association Between DCDC2 Polymorphisms and Risk of Dyslexia

Authors

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Rong ZhongBeifang YangHui TangLi ZouRanran SongLing-Qiang ZhuEmail authorXiaoping MiaoEmail author

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First Online: 11 December 2012

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16

Citations

Abstract

Developmental dyslexia (DD) is a highly heritable neurological disorder that is prevalent in school-aged children. The dyslexia-associated gene DCDC2 is a member of the DCX family of genes known to play roles in neurogenesis, neuronal migration, and differentiation. However, the associations between DCDC2 genetic variations and dyslexia have yielded inconclusive results. Clarifying the effects of DCDC2 polymorphisms on dyslexia risk will advance not only elucidation of the role of DCDC2 in the brain development but also development of possible therapeutic approach for dyslexia. In this review, we summarized the ongoing association studies concerning DCDC2 polymorphisms and dyslexia risk by using meta-analysis and revealed that DCDC2 rs807701 might contribute significantly to dyslexia risk.

Gostic, M., Martinelli, A., Tucker, C., Yang, Z., Gasparoli, F., Dholakia, K., … & Paracchini, S. (2018). The dyslexia susceptibility KIAA0319 gene shows a highly specific expression pattern during zebrafish development supporting a role beyond neuronal migration. bioRxiv, 267617.

Dyslexia is a common neurodevelopmental disorder caused by a significant genetic

component. The KIAA0319 gene is one of the most robust dyslexia susceptibility factors but its function remains poorly understood. Initial RNA-interference studies in

rats suggested a role in neuronal migration whereas subsequent work with double

knock-out mouse models for both Kiaa0319 and its paralogue Kiaa0319-like reported

effects in the auditory system but not in neuronal migration. To further understand

the role of KIAA0319 during neurodevelopment, we carried out an expression study

of its zebrafish orthologue at different embryonic stages. We used different

approaches including RNAscope in situ hybridization combined with light-sheet

microscopy. The results show particularly high expression during the first few hours

of development. Later, expression becomes localized in well-defined structures. In

addition to high expression in the brain, we report for the first time expression in the

eyes and the notochord. Surprisingly, kiaa0319-like, which generally shows a similar

expression pattern to kiaa0319, was not expressed in the notochord suggesting a distinct role for kiaa0319 in this structure. This observation was supported by the identification of notochord enhancers enriched upstream of the KIAA0319 transcription

start site, in both zebrafish and humans. This study supports a developmental role for

KIAA0319 in the brain as well as in other developing structures, particularly

DYX1C1 is required for axonemal dynein assembly and ciliary motility

Schmitz, J., Kumsta, R., Moser, D., Güntürkün, O., & Ocklenburg, S. (2018). KIAA0319 promoter DNA methylation predicts dichotic listening performance in forced-attention conditions. Behavioural brain research, 337, 1-7.

Metalli pesanti

Come si legge nel decreto di sequestro preventivo del Tribunale di Taranto, nell’aria della città pugliese è stata rilevata la presenza di «composti inorganici aerodispersi prevalentemente a base di ferro e ossidi di ferro (materia prima essenziale nei processi siderurgici)», oltre che di metalli pesanti tossici tra cui l’arsenico. ci sono molibdeno, nichel, piombo, rame, selenio, vanadio, zinco e platino. la presenza di piombo nelle urine dei tarantini

PM10 e PM2,5 (Particulate Matter o materia particolata)

La materia particolata è una miscela di elementi metallici e composti chimici organici e inorganici dotati di differente tossicità per l’uomo. Il 10 o il 2,5 dopo l’acronimo Pm identificano il diametro delle particelle, 10 o 2,5 millesimi di millimetro.

Gas (NO2, SO2)

Attraverso le “torce” dell’acciaieria, si legge nelle perizie, l’impianto avrebbe smaltito «abusivamente una gran quantità di rifiuti gassosi». Le sostanze inquinanti aerodisperse con un impatto negativo «rilevante» sulla salute dell’uomo, e in modo specifico sull’apparato respiratorio raggiunto per via inalatoria, sono gli ossidi di zolfo, in particolare SO2, e gli ossidi di azoto, in particolare NO2. A questi si aggiungono l’ossido di carbonio, gli idrocarburi aromatici policiclici e il particolare totale sospeso.

L’esposizione al diossido di azoto, NO2, nell’area di residenza è associata a sintomi di bronchite anche negli adulti. Il composto è un forte irritante delle vie polmonari: provoca tosse acuta, dolori al torace, convulsione e insufficienza respiratoria. I danni ai polmoni si possono manifestare anche molti mesi dopo l’esposizione. Il diossido di zolfo, SO2, o anidride solforosa, è un gas irritante per gli occhi e per il tratto respiratorio. Per inalazione può causare edema polmonare e una prolungata esposizione può portare anche alla morte.

Idrocarburi policiclici aromatici (Ipa)

Sono un gruppo di composti chimici simili per struttura, formati da più anelli aromatici condensati in una struttura piana. Tra i più tossici: antracene, acenaftene, benzo(a)pirene, benzo(j)fluorantene, fenantrene, crisene.

Nello stabilimento dell’Ilva il punto di maggior emissione di diossine è il camino. Diossine

Sono una classe di composti organici eterociclici. Comprendono un gruppo di 210 composti aromatici clorurati classificabili in due grandi famiglie: le PoliCloroDibenzoDiossine (Pcdd) e i PoliCloroDibenzoFurani (Pcdf), che hanno struttura chimica, azione biologica e proprietà fisiche simili. Rientrano in questa classe anche i PoliCloroBifenili, Pcb, o diossina-simili (o Pcb-dl dioxine like) per le proprietà tossicologiche comuni.

Chlamydomonas DYX1C1/PF23 is essential for axonemal assembly and proper morphology of inner dynein arms

Ryosuke Yamamoto , Jagan M. Obbineni , Lea M. Alford, Takahiro Ide, Mikito Owa, Juyeon Hwang, Takahide Kon, Kazuo Inaba, Noliyanda James, Stephen M. King, Takashi Ishikawa , Winfield S. Sale , Susan K. Dutcher

DYX1C1 is essential for the assembly of the majority of ciliary inner dynein arms (IDA) as well as a fraction of the outer dynein arms (ODA). A C-terminal truncation of DYX1C1 shows a reduction in a subset of these ciliary IDAs. Sucrose gradients of cytoplasmic extracts show that preassembled ciliary dyneins are reduced compared to wild-type, which suggests an important role in dynein complex stability. The role of PF23/DYX1C1 remains unknown, but we suggest that DYX1C1 could provide a scaffold for macromolecular assembly.

Neurobiology of Dyslexia
Elizabeth S. Norton1, Sara D. Beach1, and John D. E. Gabrieli1,2

1McGovern Institute for Brain Research, and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 43 Vassar St., Cambridge, MA 02139

2Institute for Medical Engineering & Science, Cambridge, MA 02139

Abstract

Dyslexia is one of the most common learning disabilities, yet its brain basis and core causes are not yet fully understood. Neuroimaging methods, including structural and functional magnetic resonance imaging, diffusion tensor imaging, and electrophysiology, have significantly contributed to knowledge about the neurobiology of dyslexia. Recent studies have discovered brain differences prior to formal instruction that likely encourage or discourage learning to read effectively, distinguished between brain differences that likely reflect the etiology of dyslexia versus brain differences that are the consequences of variation in reading experience, and identified distinct neural networks associated with specific psychological factors that are associated with dyslexia.

The molecular genetics and neurobiology of developmental dyslexia as model of a complex phenotype

Juha Kere ⇑
Department of Biosciences and Nutrition, Centre for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden

Molecular Neurology Research Program, University of Helsinki, Folkhälsan Institute of Genetics, Helsinki, Finland

article info

Article history:

Received 27 June 2014 Available online 28 July 2014

Keywords:

Reading disability Neuronal migration Cilia function White matter Cognitive function

Contents

abstract

Among complex disorders, those concerning neuropsychiatric phenotypes involve particular challenges compared to disorders with more easily distinguished clinical signs and measures. One such common and unusually challenging phenotype to disentangle genetically is developmental dyslexia (DD), or read- ing disability, defined as the inability to learn to read and write for an otherwise normally intelligent child with normal senses and educational opportunity. There is presently ample evidence for the strongly biological etiology for DD, and a dozen susceptibility genes have been suggested. Many of these genes point to common but previously unsuspected biological mechanisms, such as neuronal migration and cilia functions. I discuss here the state-of-the-art in genomic and neurobiological aspects of DD research, starting with short general background to its history.

Ó 2014 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license

Genetics of developmental dyslexia

Thomas S. Scerri • Gerd Schulte-Ko ̈rne

Received: 10 July 2009 / Accepted: 15 November 2009 / Published online: 29 November 2009 Ó Springer-Verlag 2009

Abstract Developmental dyslexia is a highly heritable disorder with a prevalence of at least 5% in school-aged children. Linkage studies have identified numerous loci throughout the genome that are likely to harbour candidate dyslexia susceptibility genes. Association studies and the refinement of chromosomal translocation break points in individuals with dyslexia have resulted in the discovery of candidate genes at some of these loci. A key function of many of these genes is their involvement in neuronal migration. This complements anatomical abnormalities discovered in dyslexic brains, such as ectopias, that may be the result of irregular neuronal migration.

Insights into the Genetic Foundations of Human Communication Sarah A. Graham & Pelagia Deriziotis & Simon E. Fisher

Received: 5 September 2014 / Accepted: 22 December 2014 / Published online: 18 January 2015 # Springer Science+Business Media New York 2015

Abstract The human capacity to acquire sophisticated lan- guage is unmatched in the animal kingdom. Despite the dis- continuity in communicative abilities between humans and other primates, language is built on ancient genetic founda- tions, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisi- tion. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communi- cative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroim- aging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future en- deavors to bridge the gaps between genes, brains and behavior.

Keywords Communication . Speech and language . Neurodevelopmental disorder . Genetics . FOXP2

Behavioral/Cognitive

Glutamate and Choline Levels Predict Individual Differences in Reading Ability in Emergent Readers

Kenneth R. Pugh,1,2,3 Stephen J. Frost,1 Douglas L. Rothman,2 Fumiko Hoeft,1,4 Stephanie N. Del Tufo,1,3
Graeme F. Mason,2 Peter J. Molfese,1 W. Einar Mencl,1 Elena L. Grigorenko,1,5 Nicole Landi,1,3,5 Jonathan L. Preston,1,6 Leslie Jacobsen,1 Mark S. Seidenberg,1,7 and Robert K. Fulbright1,2
1Haskins Laboratories, New Haven, Connecticut 06511, 2Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520-8042, 3Department of Psychology, University of Connecticut, Storrs, Connecticut 06269-1020, 4Department of Psychiatry, University of California San Francisco, San Francisco, California 94143-0984, 5Yale University Child Study Center, New Haven, Connecticut 06520, 6Department of Communication Disorders, Southern Connecticut State University, New Haven, Connecticut 06515, and 7Department of Psychology, University of Wisconsin Madison, Madison, Wisconsin 53706-1611

Reading disability is a brain-based difficulty in acquiring fluent reading skills that affects significant numbers of children. Although neuroanatomical and neurofunctional networks involved in typical and atypical reading are increasingly well characterized, the under- lying neurochemical bases of individual differences in reading development are virtually unknown. The current study is the first to examine neurochemistry in children during the critical period in which the neurocircuits that support skilled reading are still developing. In a longitudinal pediatric sample of emergent readers whose reading indicators range on a continuum from impaired to superior, we examined the relationship between individual differences in reading and reading-related skills and concentrations of neurometabolites measured using magnetic resonance spectroscopy. Both continuous and group analyses revealed that choline and glutamate concentra- tions were negatively correlated with reading and related linguistic measures in phonology and vocabulary (such that higher concentra- tions were associated with poorer performance). Correlations with behavioral scores obtained 24 months later reveal stability for the relationship between glutamate and reading performance. Implications for neurodevelopmental models of reading and reading disabil- ity are discussed, including possible links of choline and glutamate to white matter anomalies and hyperexcitability. These findings point to new directions for research on gene-brain-behavior pathways in human studies of reading disability.

REVIEW ARTICLE

The impact of music on auditory and speech processing Abdollah Moossavi1, Nasrin Gohari2,3*

1- Department of Otolaryngology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
2- Department of Audiology, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
3- Department of Audiology, School of Rehabilitation, Hamadan University of Medical Sciences, Hamadan, Iran

Received: 22 Sep 2018, Revised: 27 Oct 2018, Accepted: 11 Nov 2018, Published: 15 Jul 2019

Abstract
Background and Aim: Researchers in the fields of psychoacoustic and electrophysiology are mostly focused on demonstrating the better and different neurophysiological performance of musicians. The present study explores the imp- act of music upon the auditory system, the non- auditory system as well as the improvement of language and cognitive skills following listening to music or receiving music training.
Recent Findings: Studies indicate the impact of music upon the auditory processing from the cochlea to secondary auditory cortex and other parts of the brain. Besides, the impact of music on speech perception and other cognitive proce- ssing is demonstrated. Some papers point to the bottom-up and some others to the top-down pro- cessing, which is explained in detail. Conclusion: Listening to music and receiving music training, in the long run, creates plasticity from the cochlea to the auditory cortex. Since the auditory path of musical sounds overlaps functionally with that of speech path, music hel- ps better speech perception, too. Both percep- tual and cognitive functions are involved in this process. Music engages a large area of the brain, so music can be used as a supplement in rehabi- litation programs and helps the improvement of speech and language skills.

The molecular genetics and neurobiology of developmental dyslexia as model of a complex phenotype

Juha Kere ⇑
Department of Biosciences and Nutrition, Centre for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden

Molecular Neurology Research Program, University of Helsinki, Folkhälsan Institute of Genetics, Helsinki, Finland

article info

Article history:

Received 27 June 2014 Available online 28 July 2014

Keywords:

Reading disability Neuronal migration Cilia function White matter Cognitive function

Contents

abstract

Among complex disorders, those concerning neuropsychiatric phenotypes involve particular challenges compared to disorders with more easily distinguished clinical signs and measures. One such common and unusually challenging phenotype to disentangle genetically is developmental dyslexia (DD), or read- ing disability, defined as the inability to learn to read and write for an otherwise normally intelligent child with normal senses and educational opportunity. There is presently ample evidence for the strongly biological etiology for DD, and a dozen susceptibility genes have been suggested. Many of these genes point to common but previously unsuspected biological mechanisms, such as neuronal migration and cilia functions. I discuss here the state-of-the-art in genomic and neurobiological aspects of DD research, starting with short general background to its history.

Article

Music Training Positively Influences the Preattentive Perception of Voice Onset Time in Children with Dyslexia: A Longitudinal Study

Aline Frey 1,* , Clément François 2,3, Julie Chobert 4, Jean-Luc Velay 4, Michel Habib 5 and Mireille Besson 4,6

* Correspondence: aline.frey@u-pec.fr; Tel.: +01-49-56-35-27

Received: 1 April 2019; Accepted: 13 April 2019; Published: 21 April 2019

ESPE de l’académie de Créteil, Université Paris-Est Créteil, Laboratoire CHArt, 94380 Bonneuil-sur-Marne, France
Laboratoire Parole et Langage, CNRS et Aix Marseille Université, 13640 Aix-en-Provence, France; fclement24@hotmail.com

Cognition and Brain Plasticity Group, IDIBELL, University of Barcelona, 08193 Barcelona, Spain Laboratoire de Neurosciences Cognitives, CNRS et Aix-Marseille Université, 13331 Marseille, France; julie@chobert.fr (J.C.); jean-luc.velay@univ-amu.fr (J.-L.V.); mireille.besson@univ-amu.fr (M.B.) Département de Neurologie Pédiatrique, CHU Timone, 13005 Marseille, France; michel.habib@resodys.org Cuban Neuroscience Center, La Havane 4850, Cuba

Abstract: Previous results showed a positive influence of music training on linguistic abilities at

both attentive and preattentive levels. Here, we investigate whether six months of active music training is more efficient than painting training to improve the preattentive processing of phonological parameters based on durations that are often impaired in children with developmental dyslexia (DD). Results were also compared to a control group of Typically Developing (TD) children matched on reading age. We used a Test–Training–Retest procedure and analysed the Mismatch Negativity (MMN) and the N1 and N250 components of the Event-Related Potentials to syllables that differed in Voice Onset Time (VOT), vowel duration, and vowel frequency. Results were clear-cut in showing a normalization of the preattentive processing of VOT in children with DD after music training but not after painting training. They also revealed increased N250 amplitude to duration deviant stimuli in children with DD after music but not painting training, and no training effect on the preattentive processing of frequency. These findings are discussed in view of recent theories of dyslexia pointing to deficits in processing the temporal structure of speech. They clearly encourage the use of active music training for the rehabilitation of children with language impairments.

Neural Noise Hypothesis of Developmental Dyslexia
Roeland Hancock, PhD1, Kenneth R. Pugh, PhD2,3,4,5, and Fumiko Hoeft, MD, PhD1,2,6

1Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco (UCSF). 401 Parnassus Ave. Box-0984, San Francisco, CA 94143

2Haskins Laboratories. 300 George Street, New Haven, CT 06511
3Department of Linguistics, Yale University. 370 Temple Street, New Haven, CT 06520

4Department of Radiology and Biomedical Imaging, Yale University. 330 Cedar Street, New Haven, CT 06520

5Department of Psychological Sciences, University of Connecticut. 406 Babbidge Road, Storrs, CT 06269

6Department of Neuropsychiatry, Keio University School of Medicine. 35 Shinanomachi, Shinjuku- ku, Tokyo, Japan 160

Abstract

Developmental dyslexia (decoding-based reading disorder; RD) is a complex trait with multifactorial origins at the genetic, neural and cognitive levels. There is evidence that low-level sensory processing deficits precede and underlie phonological problems, which are one of the best-documented aspects of RD. RD is also associated with impairments in integrating visual symbols with their corresponding speech sounds. Although causal relationships between sensory processing, print-speech integration and fluent reading, and their neural bases are debated, these processes all require precise timing mechanisms across distributed brain networks. Neural excitability and neural noise are fundamental to these timing mechanisms. We propose that neural noise stemming from increased neural excitability in cortical networks implicated in reading is one key, distal contributor to RD.

Keywords

Reading; neural oscillation; neurogenetics; excitability; glutamate

Neurobiology of dyslexia : A reinterpretation of the data

Franck Ramus1,2

1 Laboratoire de Sciences Cognitives et Psycholinguistique (EHESS/CNRS/ENS), 46 rue d’Ulm, 75230 Paris Cedex 5, France
2 Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London WC1N 3AR, UK
Correspondence: franck.ramus@ens.fr

Keywords

dyslexia, specific language impairment, sensory deficits, motor impairment, magnocellular dysfunction, ectopias.

Teaser

A new model that attempts to explain how a specific phonological deficit may arise from genetically determined brain anomalies, in isolation in certain individuals, and together with sensorimotor impairments in others.

Abstract

Theories of developmental dyslexia differ on how to best interpret the great variety of symptoms (linguistic, sensory, motor) observed in dyslexic individuals. One approach views dyslexia as a specific phonological deficit, which sometimes co-occurs with a more general sensorimotor syndrome. The present review of the neurobiology of dyslexia shows that neurobiological data are indeed consistent with this view, explaining both how a specific phonological deficit might arise, and why a sensorimotor syndrome should be significantly associated with it. This new conceptualisation of the aetiology of dyslexia may generalise to other neuro-developmental disorders, and may further explain heterogeneity within each disorder and co-morbidity between disorders.

REVIEW ARTICLE

The neuronal migration hypothesis of dyslexia: A critical evaluation 30 years on

Luiz G. Guidi1,2 | Antonio Velayos-Baeza1,2 Anthony P. Monaco4 | Silvia Paracchini5

 

Abstract

The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiologi- cal mechanisms that mediate normal or impaired linguistic ability. For developmen- tal dyslexia, early postmortem studies conducted in the 1980s linked the disorder to subtle defects in the migration of neurons in the developing neocortex. These early studies were reinforced by human genetic analyses that identified dyslexia suscepti- bility genes and subsequent evidence of their involvement in neuronal migration. In this review, we examine recent experimental evidence that does not support the link between dyslexia and neuronal migration. We critically evaluate gene function stud- ies conducted in rodent models and draw attention to the lack of robust evidence from histopathological and imaging studies in humans. Our review suggests that the neuronal migration hypothesis of dyslexia should be reconsidered, and the neurobio- logical basis of dyslexia should be approached with a fresh start.

The dyslexia-associated gene Dcdc2 is required for spike-timing precision in mouse neocortex

Alicia Che, Matthew J. Girgenti, and Joseph LoTurco
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269

Abstract

Background—Variants in dyslexia-associated genes, including DCDC2, have been linked to altered neocortical activation, suggesting that dyslexia associated genes may play as of yet unspecified roles in neuronal physiology.

Methods—Whole-cell patch clamp recordings were used to compare the electrophysiological properties of regular spiking (RS) pyramidal neurons of neocortex in Dcdc2 knock out (KO) and wild-type (WT) mice. RNA-seq and RT-PCR were performed to identify and characterize changes in gene expression in Dcdc2 KOs.

Results—Neurons in KOs showed increased excitability and decreased temporal precision in action potential (AP) firing. The RNA-seq screen revealed that the N-methyl-D-aspartate receptor (NMDAR) subunit Grin2B was elevated in Dcdc2 KOs, and an electrophysiological assessment confirmed a functional increase in spontaneous NMDAR-mediated activity. Remarkably, the decreased AP temporal precision could be restored in mutants by treatment with either the NMDAR antagonist APV or the NMDAR 2B subunit (NR2B)-specific antagonist Ro 25-6981.

Conclusions—These results link the function of the dyslexia-associated gene Dcdc2 to spike timing through activity of NMDAR.

Dyslexia risk gene relates to representation of sound in the auditory brainstem

Nicole E. Neefa,∗, Bent Müllerb, Johanna Liebiga, Gesa Schaadta,c, Maren Grigutscha, Thomas C. Guntera, Arndt Wilckeb, Holger Kirstenb,d, Michael A. Skeidea, Indra Krafta, Nina Krause, Frank Emmrichb, Jens Brauera, Johannes Boltzeb,f, Angela D. Friedericia

a Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany
b Department of Cell Therapy, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
c Department of Psychology, Humboldt-Universität zu Berlin, 12489 Berlin, Germany
d Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig and LIFE—Leipzig Research Center for Civilization Diseases, University of Leipzig, Germany

e Auditory Neuroscience Laboratory, Northwestern University, Evanston, IL 60208, USA
f Department of Medical Cell Technology, Fraunhofer Research Institution for Marine Biotechnology, and Institute for Medical and Marine Biotechnology, University of Lübeck, Germany

article info

Article history:

Received 26 September 2016
Received in revised form 15 January 2017 Accepted 15 January 2017
Available online 17 January 2017

Keywords:

Developmental dyslexia

KIAA0319
DCDC2
Brainstem responses Sound processing Genetic risk

1. Introduction

Dyslexia is characterized by poor reading, writing, and spelling skills despite typical intelligence, no visual acuity problems, and appropriate education (ICD-10-CM, http://www.icd10data.com/ ICD10CM/Codes/F01-F99/F80-F89/F81-/F81.0). Boys are 2–3 times more likely to be affected than girls, and cumulative incidence rates vary from 5–12% (Shaywitz et al., 1990). Dyslexia persists in 4–6% of adults (Schulte-Körne and Remschmidt, 2003) disad- vantaging employment, and compromising participation in public

∗ Corresponding author.
E-mail address: neef@cbs.mpg.de (N.E. Neef).

abstract

Dyslexia is a reading disorder with strong associations with KIAA0319 and DCDC2. Both genes play a functional role in spike time precision of neurons. Strikingly, poor readers show an imprecise encoding of fast transients of speech in the auditory brainstem. Whether dyslexia risk genes are related to the quality of sound encoding in the auditory brainstem remains to be investigated. Here, we quantified the response consistency of speech-evoked brainstem responses to the acoustically presented syllable [da] in 159 genotyped, literate and preliterate children. When controlling for age, sex, familial risk and intelligence, partial correlation analyses associated a higher dyslexia risk loading with KIAA0319 with noisier responses. In contrast, a higher risk loading with DCDC2 was associated with a trend towards more stable responses. These results suggest that unstable representation of sound, and thus, reduced neural discrimination ability of stop consonants, occurred in genotypes carrying a higher amount of KIAA0319 risk alleles. Current data provide the first evidence that the dyslexia-associated gene KIAA0319 can alter brainstem responses and impair phoneme processing in the auditory brainstem. This brain-gene relationship provides insight into the complex relationships between phenotype and genotype thereby improving the understanding of the dyslexia-inherent complex multifactorial condition.

From The Department of Biosciences and Nutrition Karolinska Institutet, Stockholm, Sweden

IDENTIFICATION OF SUSCEPTIBILITY GENES FOR DYSLEXIA

Heidi Anthoni

Developmental dyslexia, also known as specific reading disability, is characterized by persistent difficulties in learning to read and spell in spite of adequate intelligence, education, social environment, and normal senses. It is the most common learning disability affecting 5-10% of school-aged children. The core deficit in dyslexia is believed to involve phonological processing. Dyslexia has a complex genetic basis, and family studies as well as extensive molecular genetic studies have proven the importance of genetic factors in the development of this disorder. To date, nine chromosomal regions have been identified as susceptibility loci for dyslexia; DYX1– DYX9. DYX1C1 on chromosome 15q21 was the first candidate gene suggested based on the cloning of a translocation breakpoint co-segregating with dyslexia.

The aim of this thesis project was to identify susceptibility genes for dyslexia primarily by using a positional cloning approach. Specifically, three candidate loci for dyslexia were studied; DYX1, DYX2, and DYX3. Several rounds of genetic mapping within the DYX3 region lead to the identification of overlapping dyslexia risk haplotypes in two independent sample sets. Carriers of the risk haplotype showed attenuated expression of two co-expressed genes within the region, MRPL19 and C2ORF3, indicating a possible regulatory effect of the risk variants. Linkage disequilibrium mapping within the most replicated susceptibility for dyslexia, DYX2, revealed a strong genetic effect for DCDC2 in dyslexic individuals, in particular in more severely affected cases. The effect of this gene as a susceptibility factor for dyslexia was confirmed by replication analysis in an independent sample set.

Replication efforts of DYX1C1 have shown inconsistent results, and thus its role in the development of dyslexia has been considered unsettled. We refined the haplotype structure by analyzing additional variants within the DYX1C1 locus. The haplotypes showed association with dyslexia in a large sample set, with possible sex-specific effects. Refined mapping of another translocation within the DYX1 region co- segregating with dyslexia located the breakpoint to the complex promoter region of CYP19A1 (aromatase). Genetic variation within CYP19A1 associated with speech and language measures and dyslexia in three independent sample sets. Variation in the highly conserved brain promoter of CYP19A1 altered transcription factor binding. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. Brain morphology studies of aromatase-deficient mice showed increased cortical neuronal density and occasional cortical heterotopias, similar to those observed in human dyslexic brains.

To date, seven candidate susceptibility genes have been suggested for dyslexia. In addition to the ones studied in this thesis, KIAA0319 within DYX2 and ROBO1 within DYX5 have been indicated in dyslexia. Studies of the dyslexia candidate genes in rats and mice implicate neuronal migration and axon guidance as neurobiological mechanisms that likely mediate this disorder. Anatomical studies support this hypothesis as cortical abnormalities have been observed in dyslexic brains. Functional brain imaging studies show that these disrupted areas are involved in phonological processing and display abnormal activation in dyslexics. Taken together, our results and these studies implicate a biological basis for developmental dyslexia.

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