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

doi:10.1016/j.biopsych.2013.08.018

Biological Psychiatry

Volume 76, Issue 5, 1 September 2014, Pages 387-396

https://doi.org/10.1016/j.biopsych.2013.08.018 Get rights and content

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.

Section snippets

Slice Preparation

The P18-P28 WT and Dcdc2 KO mice were deeply anesthetized with isoflurane and then decapitated. All experiments were performed under the approval of the University of Connecticut Animal Care and Use Committee. Brains were rapidly removed and immersed in ice-cold oxygenated (95% oxygen and 5% carbon dioxide) dissection buffer containing (in mmol/L): 83 sodium chloride, 2.5 potassium chloride, 1 sodium dihydrogenorthophosphate, 26.2 sodium bicarbonate, 22 glucose, 72 sucrose, .5 calcium chloride,

Increased Spike Rate and Decreased Spike Timing Precision in Dcdc2 KOs

Neuronal spike rates and temporal patterns together encode stimulus features and stimulus change 18, 19, 20, 21. We therefore assessed both spike rate and spike time precision in neocortical pyramidal neurons in WT and Dcdc2 KOs. The rates of APs generated by a range of supra-threshold current steps were significantly increased in KO neurons compared with WT neurons (repeated measures ANOVA [between variables: genotype; within variables: current step], main effect of genotype: F_1,36 = 9.34, p <

Discussion

Several electrophysiological properties influence the temporal precision of APs in central neurons, including nonlinearity of membrane conductances at threshold 26, 27, 28 and synaptic noise 29, 30. Spontaneous synaptic noise can either enhance or reduce the temporal precision of spike trains, depending on their features [review see Ermentrout et al. (31)]. In cortical regular spiking neurons specifically, the type of background synaptic conductance added can affect the gain and variability in

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Animal models of developmental dyslexia: Where we are and what we are missing
2021, Neuroscience and Biobehavioral Reviews
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These results suggest that Dcdc2 genetic loss is not solely responsible for creating abnormalities in neuronal migration or differentiation in the neocortex; rather, Dcdc2 may have partial functional redundancy with Dcx (Coquelle et al., 2006; Reiner et al., 2006) in regulating neuronal migration and dendritic growth (Wang et al., 2011). At the functional neuronal level, Dcdc2 KO mice had increased excitability and decreased temporal precision in action potential firing in the pyramidal neurons of the neocortex compared to WT mice (Che et al., 2014). Subsequent studies showed that increased functional excitatory connectivity between layer 4 and the lateral connections in the somatosensory neocortex is mediated by the N-methyl-d-aspartate receptor (NMDAR) subunit Grin2B (Che et al., 2014, 2016).
Developmental dyslexia (DD) is a complex neurodevelopmental disorder and the most common learning disability among both school-aged children and across languages. Recently, sensory and cognitive mechanisms have been reported to be potential endophenotypes (EPs) for DD, and nine DD-candidate genes have been identified. Animal models have been used to investigate the etiopathological pathways that underlie the development of complex traits, as they enable the effects of genetic and/or environmental manipulations to be evaluated. Animal research designs have also been linked to cutting-edge clinical research questions by capitalizing on the use of EPs. For the present scoping review, we reviewed previous studies of murine models investigating the effects of DD-candidate genes. Moreover, we highlighted the use of animal models as an innovative way to unravel new insights behind the pathophysiology of reading (dis)ability and to assess cutting-edge preclinical models.
Visual attention and neural oscillations in reading and dyslexia: Are they possible targets for remediation?
2019, Neuropsychologia
Citation Excerpt :
Such effects, if substantiated by further studies, may indicate that the direct current while not directly affecting any oscillatory activity at any particular frequency, may have a general effect of altering the glutamatergic activity and thus changing the excitation/inhibition balance in a direction to facilitate a more appropriate neuronal oscillatory behaviour in the area stimulated. In fact, two genes implicated in a reading disorder, namely DCDC2 and KIAA0319 (Paracchini et al., 2007; Gori et al., 2015; Mascheretti et al., 2018) are both known to affect glutamate activity and their deletions in the mouse lead to increased activity in the excitatory glutamatergic neurons (Centanni et al., 2014; Che et al., 2014), potentially causing higher neural noise in reading related functions (Hancock et al., 2017). However, in the light of the reservations expressed earlier, it remains to be seen whether delivering sufficient currents at the relevant cortical structures without causing unpleasant and harmful side effects is at all feasible.
After decades of finding a range of cognitive functions both in visual and phonological domains that correlate with reading performance, there are in recent years attempts to solve the causation versus correlation dilemma in finding a core deficit in developmental dyslexia (DD). Thus, longitudinal studies that aim to predict reading difficulties from studies done in pre-reading years and reading-level matched studies that try to factor out the effect due to lack of reading in DD cohorts, have helped identify two possible candidates to be added to the classical phonological suspect. One is a deficit in visuo-spatial attention that underpins our ability to selectively attend to individual objects in a cluttered world, which is fundamental in being able to identify letters and words in a text such as the one you are reading now. The other is an impairment in synchronised neuronal oscillations that may be crucial in mediating many cortical functions and also communication between brain regions. The latter may be a general deficit affecting many areas of the brain and thus underlie the wide-ranging co-morbidities in DD. However, that neuronal synchrony is a critical mediator in visual attention, brings the two suggestions into one hypothesis of a core deficit that triggers in some young children a great reluctance to read, putting them at a handicap in comparison to other children. This deprives them of the advantage that normal readers have in development of those visual and phonological processes that are needed for reading. This insight into aetiology may help in developing new remediation strategies, specifically aimed at improving visual attention and neuronal synchrony.
Neural Noise Hypothesis of Developmental Dyslexia
2017, Trends in Cognitive Sciences
Citation Excerpt :
Evidence that DCDC2 modifies neural activity within the excitatory glutamatergic pathway implicates increased neural excitability as a source of neural noise in RD. Mice with reduced or disabled function of the homologous Dcdc2 gene have increased release of glutamate, expression of glutamate [N-methyl-D-aspartate (NMDA)] receptor genes, NMDA excitability and spontaneous activity, and spike timing variability [5,56] in cortical neurons. These phenotypes can be rescued using NMDA antagonists [5]. Other Dcdc2 animal models show impaired rapid auditory processing [3,8], similar to the deficits found in children at risk for RD [57].
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. Here, we propose that neural noise stemming from increased neural excitability in cortical networks implicated in reading is one key distal contributor to RD.
Dyslexia risk gene relates to representation of sound in the auditory brainstem
2017, Developmental Cognitive Neuroscience
Citation Excerpt :
This indicates better phase-locking capabilities of neurons in the auditory midbrain in carriers of DCDC2 risk alleles. However, a different animal study showed that a Dcdc2 knockout impaired temporal encoding as evident in degraded neural spike timing during the encoding of rapid sequential sensory inputs to the somatosensory cortex (Che et al., 2014). This discrepancy might be disentangled on the background of above elaborated trans-gene interactions suggesting that certain DCDC2 haplotypes regulate KIAA0319 expression resulting in opposing behavioral effects.
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.
Why is the processing of global motion impaired in adults with developmental dyslexia?
2016, Brain and Cognition
Individuals with dyslexia are purported to have a selective dorsal stream impairment that manifests as a deficit in perceiving visual global motion relative to global form. However, the underlying nature of the visual deficit in readers with dyslexia remains unclear. It may be indicative of a difficulty with motion detection, temporal processing, or any task that necessitates integration of local visual information across multiple dimensions (i.e. both across space and over time). To disentangle these possibilities we administered four diagnostic global motion and global form tasks to a large sample of adult readers (N = 106) to characterise their perceptual abilities. Two sets of analyses were conducted. First, to investigate if general reading ability is associated with performance on the visual tasks across the entire sample, a composite reading score was calculated and entered into a series of continuous regression analyses. Next, to investigate if the performance of readers with dyslexia differs from that of good readers on the visual tasks we identified a group of forty-three individuals for whom phonological decoding was specifically impaired, consistent with the dyslexic profile, and compared their performance with that of good readers who did not exhibit a phonemic deficit. Both analyses yielded a similar pattern of results. Consistent with previous research, coherence thresholds of poor readers were elevated on a random-dot global motion task and a spatially one-dimensional (1-D) global motion task, but no difference was found on a static global form task. However, our results extend those of previous studies by demonstrating that poor readers exhibited impaired performance on a temporally-defined global form task, a finding that is difficult to reconcile with the dorsal stream vulnerability hypothesis. This suggests that the visual deficit in developmental dyslexia does not reflect an impairment detecting motion per se. It is better characterised as a difficulty processing temporal information, which is exacerbated when local visual cues have to be integrated across multiple (>2) dimensions.
Genetic and protein interaction studies between the ciliary dyslexia candidate genes DYX1C1 and DCDC2
2023, BMC Molecular and Cell Biology

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

Background

Methods

Results

Conclusions

Section snippets

Slice Preparation

Increased Spike Rate and Decreased Spike Timing Precision in Dcdc2 KOs

Discussion

Lancet

Am J Hum Genet

Neuroimage

Biol Psychiatry

Neuroscience

Biophys J

Neuron

Neurosci Lett

Neuron

Trends Neurosci

Neuroscience

Trends Neurosci

Neuroscience

Neuron

Curr Opin Neurobiol

Trends Cogn Sci

J Biol Chem

Gene by environment interactions influencing reading disability and the inattentive symptom dimension of attention deficit/hyperactivity disorder

J Child Psychol Psychiatry

DCDC2 is associated with reading disability and modulates neuronal development in the brain

Proc Natl Acad Sci U S A

Genetic variant in KIAA0319, but not in DYX1C1, is associated with risk of dyslexia: An integrated meta‐analysis

Am J Med Genet

Meta-analysis of the association between DCDC2 polymorphisms and risk of dyslexia

Mol Neurobiol

Polymorphism of DCDC2 reveals differences in cortical morphology of healthy individuals—a preliminary voxel based morphometry study

Brain Imaging Behav

Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions

J Neurosci

The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration

Hum Mol Genet

Mutation of the dyslexia-associated gene Dcdc2 impairs LTM and visuo-spatial performance in mice

Genes Brain Behav

Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex [published online ahead of print February 8]

Cereb Cortex

Reliability of spike timing in neocortical neurons

Science

The action potential in mammalian central neurons

Nat Rev Neurosci

Millisecond encoding precision of auditory cortex neurons

Proc Natl Acad Sci U S A

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