The Dyslexia-Associated Gene Dcdc2 Is Required for Spike-Timing Precision in Mouse Neocortex

BACKGROUND Variants in dyslexia-associated genes, including DCDC2, have been linked to altered neocortical activation, suggesting that dyslexia associated genes might play as yet unspecified roles in neuronal physiology. METHODS Whole-cell patch clamp recordings were used to compare the electrophysiological properties of regular spiking pyramidal neurons of neocortex in Dcdc2 knockout (KO) and wild-type mice. Ribonucleic acid sequencing and reverse transcriptase polymerase chain reaction 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 firing. The RNA sequencing 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 action potential temporal precision could be restored in mutants by treatment with either the NMDAR antagonist (2R)-amino-5-phosphonovaleric acid or the NMDAR 2B subunit-specific antagonist Ro 25-6981. CONCLUSIONS These results link the function of the dyslexia-associated gene Dcdc2 to spike timing through activity of NMDAR.

[1]  S. Lipton,et al.  Excitatory amino acids as a final common pathway for neurologic disorders. , 1994, The New England journal of medicine.

[2]  P. Skudlarski,et al.  DCDC2 is associated with reading disability and modulates neuronal development in the brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  C. Gray,et al.  Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Walsh,et al.  Patient Mutations in Doublecortin Define a Repeated Tubulin-binding Domain* , 2000, The Journal of Biological Chemistry.

[5]  G. Westbrook,et al.  Regulation of synaptic timing in the olfactory bulb by an A-type potassium current , 1999, Nature Neuroscience.

[6]  M M Merzenich,et al.  Auditory processing parallels reading abilities in adults. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Kilgard,et al.  Cortical activity patterns predict speech discrimination ability , 2008, Nature Neuroscience.

[8]  B. Müller-Myhsok,et al.  Variation in GRIN2B contributes to weak performance in verbal short‐term memory in children with dyslexia , 2010, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[9]  Paul Chen,et al.  Behavioral / Systems / Cognitive Serotonin 5-HT 1 A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism , 2005 .

[10]  Jean-Baptiste Poline,et al.  Genetic Variants of FOXP2 and KIAA0319/TTRAP/THEM2 Locus Are Associated with Altered Brain Activation in Distinct Language-Related Regions , 2012, The Journal of Neuroscience.

[11]  S. Coultrap,et al.  LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1 , 2002, Nature Neuroscience.

[12]  Wei Chen,et al.  Genetic variant in KIAA0319, but not in DYX1C1, is associated with risk of dyslexia: An integrated meta‐analysis , 2012, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[13]  M. Diamond,et al.  The Role of Spike Timing in the Coding of Stimulus Location in Rat Somatosensory Cortex , 2001, Neuron.

[14]  M. Cook,et al.  Epilepsy: Ever-changing states of cortical excitability , 2012, Neuroscience.

[15]  Vince D. Calhoun,et al.  Polymorphism of DCDC2 Reveals Differences in Cortical Morphology of Healthy Individuals—A Preliminary Voxel Based Morphometry Study , 2008, Brain Imaging and Behavior.

[16]  M P Kilgard,et al.  Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex. , 2014, Cerebral cortex.

[17]  Yun Wang,et al.  Developmental Switch in the Contribution of Presynaptic and Postsynaptic NMDA Receptors to Long-Term Depression , 2007, The Journal of Neuroscience.

[18]  Shaul Hestrin,et al.  Background synaptic conductance and precision of EPSP-spike coupling at pyramidal cells. , 2005, Journal of neurophysiology.

[19]  B. Bean.  The action potential in mammalian central neurons , 2007, Nature Reviews Neuroscience.

[20]  J D Clements,et al.  Detection of spontaneous synaptic events with an optimally scaled template. , 1997, Biophysical journal.

[21]  N. Logothetis,et al.  Millisecond encoding precision of auditory cortex neurons , 2010, Proceedings of the National Academy of Sciences.

[22]  B. Sabatini,et al.  SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines , 2005, Nature Neuroscience.

[23]  J. Byrne,et al.  More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory , 2010, Trends in Neurosciences.

[24]  Richard Wade-Martins,et al.  The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. , 2006, Human molecular genetics.

[25]  R. Todd Constable,et al.  Variants in the DYX2 locus are associated with altered brain activation in reading-related brain regions in subjects with reading disability , 2012, NeuroImage.

[26]  Frances S. Chance,et al.  Gain Modulation from Background Synaptic Input , 2002, Neuron.

[27]  Paul H. E. Tiesinga,et al.  Rapid Temporal Modulation of Synchrony by Competition in Cortical Interneuron Networks , 2004, Neural Computation.

[28]  R. Nicoll,et al.  Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. , 1989, Science.

[29]  Pierre Giraud,et al.  Spike-Time Precision and Network Synchrony Are Controlled by the Homeostatic Regulation of the D-Type Potassium Current , 2010, The Journal of Neuroscience.

[30]  D. Purpura,et al.  NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders , 2007, Nature Reviews Neuroscience.

[31]  G. Eichele,et al.  The DCX Superfamily 1: Common and Divergent Roles for Members of the Mouse DCX Superfamily , 2006, Cell cycle.

[32]  B. Philpot,et al.  Presynaptic NMDA Receptor Mechanisms for Enhancing Spontaneous Neurotransmitter Release , 2013, The Journal of Neuroscience.

[33]  A. Galaburda,et al.  Dcdc2 knockout mice display exacerbated developmental disruptions following knockdown of doublecortin , 2011, Neuroscience.

[34]  X. Miao,et al.  Meta-analysis of the Association Between DCDC2 Polymorphisms and Risk of Dyslexia , 2012, Molecular Neurobiology.

[35]  B. Pennington,et al.  Developmental dyslexia , 2012, The Lancet.

[36]  Torkel Klingberg,et al.  Three Dyslexia Susceptibility Genes, DYX1C1, DCDC2, and KIAA0319, Affect Temporo-Parietal White Matter Structure , 2012, Biological Psychiatry.

[37]  Chun-I Yeh,et al.  Temporal precision in the neural code and the timescales of natural vision , 2007, Nature.

[38]  I. Módy,et al.  Differential activation of glutamate receptors by spontaneously released transmitter in slices of neocortex , 1990, Neuroscience Letters.

[39]  P. O’Donnell.  Increased Cortical Excitability as a Critical Element in Schizophrenia Pathophysiology , 2008 .

[40]  T. Sejnowski,et al.  Synaptic background noise controls the input/output characteristics of single cells in an in vitro model of in vivo activity , 2003, Neuroscience.

[41]  Paul H. E. Tiesinga,et al.  The Possible Role of Spike Patterns in Cortical Information Processing , 2005, Journal of Computational Neuroscience.

[42]  T. Sejnowski,et al.  Regulation of spike timing in visual cortical circuits , 2008, Nature Reviews Neuroscience.

[43]  J. Stein,et al.  Auditory temporal coding in dyslexia , 1996, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[44]  E. Vreugdenhil,et al.  The doublecortin gene family and disorders of neuronal structure. , 2010, Central nervous system agents in medicinal chemistry.

[45]  Jan Wouters,et al.  Adults with dyslexia are impaired in categorizing speech and nonspeech sounds on the basis of temporal cues , 2010, Proceedings of the National Academy of Sciences.

[46]  B. Pennington,et al.  Gene by environment interactions influencing reading disability and the inattentive symptom dimension of attention deficit/hyperactivity disorder. , 2012, Journal of child psychology and psychiatry, and allied disciplines.

[47]  D. Feldman,et al.  Synapse-Specific Expression of Functional Presynaptic NMDA Receptors in Rat Somatosensory Cortex , 2008, The Journal of Neuroscience.

[48]  G A Cecchi,et al.  Noise in neurons is message dependent. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[49]  U. Goswami.  A temporal sampling framework for developmental dyslexia , 2011, Trends in Cognitive Sciences.

[50]  H. Robinson,et al.  Postsynaptic Variability of Firing in Rat Cortical Neurons: The Roles of Input Synchronization and Synaptic NMDA Receptor Conductance , 2000, The Journal of Neuroscience.

[51]  O. Prospero-Garcia,et al.  Reliability of Spike Timing in Neocortical Neurons , 1995 .

[52]  G. Ermentrout,et al.  Reliability, synchrony and noise , 2008, Trends in Neurosciences.

[53]  Andreas Ziegler,et al.  Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. , 2006, American journal of human genetics.

[54]  Franck Ramus,et al.  Altered Low-Gamma Sampling in Auditory Cortex Accounts for the Three Main Facets of Dyslexia , 2011, Neuron.

[55]  F. Ramus,et al.  Developmental dyslexia : specific phonological deficit or general sensorimotor dysfunction ? , 2003 .

[56]  M. Volgushev,et al.  Ultrafast Population Encoding by Cortical Neurons , 2011, The Journal of Neuroscience.

[57]  Bertram Müller-Myhsok,et al.  Association of a Rare Variant with Mismatch Negativity in a Region Between KIAA0319 and DCDC2 in Dyslexia , 2011, Behavior genetics.

[58]  J. Loturco,et al.  Mutation of the dyslexia‐associated gene Dcdc2 impairs LTM and visuo‐spatial performance in mice , 2011, Genes, brain, and behavior.

[59]  J. Gabrieli,et al.  Neural correlates of rapid auditory processing are disrupted in children with developmental dyslexia and ameliorated with training: an fMRI study. , 2007, Restorative neurology and neuroscience.