Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENERAL CONCLUSION <s> 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. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENERAL CONCLUSION <s> 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 underlying 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 concentrations were negatively correlated with reading and related linguistic measures in phonology and vocabulary (such that higher concentrations 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 disability 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. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENERAL CONCLUSION <s> Variants in DCDC2 have been associated with reading disability in humans, and targeted mutation of Dcdc2 in mice causes impairments in both learning and sensory processing. In this study, we sought to determine whether Dcdc2 mutation affects functional synaptic circuitry in neocortex. We found mutation in Dcdc2 resulted in elevated spontaneous and evoked glutamate release from neurons in somatosensory cortex. The probability of release was decreased to wild-type level by acute application of N-methyl-d-aspartate receptor (NMDAR) antagonists when postsynaptic NMDARs were blocked by intracellular MK-801, and could not be explained by elevated ambient glutamate, suggesting altered, nonpostsynaptic NMDAR activation in the mutants. In addition, we determined that the increased excitatory transmission was present at layer 4-layer 4 but not thalamocortical connections in Dcdc2 mutants, and larger evoked synaptic release appeared to enhance the NMDAR-mediated effect. These results demonstrate an NMDAR activation-gated, increased functional excitatory connectivity between layer 4 lateral connections in somatosensory neocortex of the mutants, providing support for potential changes in cortical connectivity and activation resulting from mutation of dyslexia candidate gene Dcdc2. <s> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | GENERAL CONCLUSION <s> 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. <s> BIB004
The findings presented in this review illustrate the complex neurobiological underpinnings of reading and language disorders (See Table 2 for a summary of results from neuroimaging genetics studies reviewed in this paper). Though the application of neuroimaging genetic methods to research on SRD and DLD is in its early stages, common threads are emerging in the observed relations among gene, brain, and behavior. Indeed, imaging genetics research has linked variation on genes involved in aspects of neurodevelopment with brain structure and/or function in language-associated areas and reading/language performance. Although these links are not as clear for genes with less wellspecified roles in neurodevelopmental processes or neuronal function, imaging genetics findings may guide new research that seeks to better understand the role of these genes in brain structure or function. Imaging genetics research also validates the involvement of a number of generalist genes, which contribute to individual differences in cognitive processing that affect reading and language performance. These contributions may explain additional genetic variance in reading and language performance beyond specific risk genes for dyslexia or DLD, thereby addressing the often-cited missing heritability problem. The associations revealed between genes and neural activation suggest genetic sources of atypical neural functioning, but it remains unclear whether functional deficits arise due to anomalous brain structure and/or direct contributions of genes to neuronal excitation and metabolism. Limited by their correlational nature, neuroimaging genetic approaches cannot directly investigate causal mechanisms of SRD and DLD in humans, but these methods are key in building theoretical models of the etiologies of these prevalent neurodevelopmental disorders. Advances in neuroimaging technologies will help to fill some gaps in the mechanisms linking genes, brain, and behavior. One promising direction is the application of magnetic resonance spectroscopy (MRS) in neurogenetic research. This noninvasive tool allows for in vivo measurement of neurometabolites and neurotransmitters, thereby providing a neurochemical level of exploration for identification of connections between genes and neural function. This method affords human investigation of evidence linking genes and neurochemistry to atypical neural function in animal models such as the association between mutation of the DCDC2 homolog in mice and altered neural activity driven by dysfunction of the neurotransmitter glutamate BIB001 BIB003 . Indeed, initial work utilizing MRS in humans has identified links between glutamate and choline and SRD and formed the basis for the application of the neural noise hypothesis to the study of SRD BIB004 BIB002 . Further insight may arise from the combined use of neuroimaging and advanced DNA sequencing methods, including next-generation whole genome sequencing and whole exome sequencing, which afford the advantage of detecting small structural variants in addition to mutations and SNPs . Ongoing developments in the use of next-generation sequencing along with advances in statistical approaches will support the discovery of new risk genes as well as complex gene by gene interactions and gene by environment interactions that further our understanding of the genetic bases of SRD and DLD. Finally, the field will benefit from continued attempts at replication of extant findings as well as data sharing and combining that will allow for mega-and meta-analyses. The aforementioned lack of replication, lack of methodological overlap, and limited details in statistical reporting pose challenges to neuroimaging genetics research, but these issues may be ameliorated through the application of rigorous research and reporting methods. With these limitations in mind, neuroimaging genetic methods can make an important contribution by helping to constrain exploratory findings through identification of intermediate phenotypes that elucidate brain-based mechanisms linking genes to behavior in SRD and DLD. Intron: A portion of the DNA sequence within a gene that does not code for proteins Linkage analysis: A method used to identify links between genetic markers (a DNA sequence in a chromosome) and traits or diseases by examining patterns of inheritance among individuals within a family who exhibit the trait of interest. Genetic markers that are specifically carried by family members who exhibit the given trait are inferred to be related to that trait and may be targeted as links to the trait in the general population. Polymorphism: A varying form of a small structural unit of the DNA molecule (a base or series of bases) which can be expressed in different forms or numbers of repetitions Sequencing: The process of identifying the order of the small units (bases) that make up DNA and genes SNP (single nucleotide polymorphism): A genetic variation in which one unit of the DNA molecule (one base) is expressed in an alternative form (e.g., G or Guanine instead of A or Adenine)