Neurodevelopmental disorders including Schizophrenia and Autism are chronic and debilitating, with relatively unknown etiology and pathophysiology. Recent progress towards understanding the genetic architecture of these disorders at the population level has led to the identification of many genetic risk factors. However, in most cases the molecular mechanism of risk and the relevant functions of the identified genes are not known and therefore identifying therapeutic targets remains difficult. In our proposal we have outlined a roadmap for the identification of therapeutic targets for psychiatric disorders and provide preliminary data that suggests our approach has merit. We will start by creating a testable cellular model of risk by genetically manipulating the expression of the schizophrenia and autism spectrum disorder gene TCF4 using in utero electroporation of the developing rat prefrontal cortex (PFC). We will then characterize the resulting neuronal phenotypes using acute brain slice electrophysiology, cell biology, and Ca2+ imaging. Such phenotypes will be evaluated as potentially pathophysiological and the development of therapeutic treatments will be based on our emerging understanding of the molecular mechanism responsible and by validating these mechanisms with molecular and pharmacological rescue or phenocopying.
In Aim1, we hypothesize that TCF4 transcriptionally regulates the expression of ion channels genes that are necessary for normal neuronal physiology and in particular channels and/or Ca2+ sensors that underlie the afterhyperpolarization (AHP). Our preliminary data suggest that in utero knockdown of TCF4 in PFC layer 2/3 pyramidal cells results in abnormal intrinsic excitability and ectopic spike-frequency adaptation. We show the mechanisms of these phenotypes are associated with an increase in the AHP and are rescued by decreasing Ca2+ influx. We propose experiments to more specifically identify the mechanisms responsible.
In Aim 2, we show that over-expression of TCF4 results in neuronal migration defects and the formation of abnormal cortical microcolumns in the developing PFC. We provide preliminary data that suggests these phenotypes may involve abnormal Eph/ephrin signaling and we hypothesize that accelerated neuronal migration will augment the development of intrinsic excitability and consequently disrupt the neuron's ability to integrate into the surrounding circuit.
In Aim 3, we provide novel RNA sequencing data from postmortem brains of schizophrenia patients and controls that identifies a specific 5'exon of TCF4 that is differentially expressed by diagnosis, associated wit GWAS positive SNPs in TCF4, and is unique to a single TCF4 isoform (TCF4H). We propose to apply this new information to our roadmap by altering TCF4H expression in utero to more effectively model schizophrenia risk and provide additional validity to cellular models. We think these innovative approaches will enable us to provide significant insights into the etiology and pathophysiology of these disorders and will ultimately open doors to novel therapeutic treatments.
Neurodevelopmental disorders such as Schizophrenia and Autism Spectrum Disorder are chronic debilitating disorders with relatively unknown etiology or pathophysiology. We are proposing to develop an in utero model of these disorders by manipulating the expression of a gene associated with risk for these two disorders. Electrophysiology, cell biology, imaging, and molecular analyses will be applied to data from this model to discover associated pathophysiology and molecular mechanisms for the development of new therapeutic treatments.
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