Abstracts

Rationale: GABAergic deficiency contributes substantially to the etiology of neurodevelopmental disorders including autism and epilepsy. Many of the disrupted genes associated with neurodevelopmental disorders contribute to the differentiation and migration of GABAergic neurons. One of these genes, neuropilin 2 (NPN2), is a receptor for class III semaphorins, a group of axonal guidance genes, that regulates migration and differentiation of hippocampal interneurons. Methods: System genetics and molecular biological approaches have been used to test the hypothesis that the extent of genetic variation in Semaphorin 3F (Sema 3F, the ligand of the NPN2 receptor) signaling contributes to changes in the formation or function of hippocampal GABAergic circuitry. Results: Distinct genetic loci, gene networks, putative transcriptional regulatory proteins of the NPN2 promoter including those linked to cAMP and PI3K/Akt signaling, and environmental toxicants (kainic acid and methylmercury) regulate variation of hippocampal NPN2 mRNA levels in genetically distinct murine strains in vivo. Consistent with our hypothesis, deletion of Semaphorin 3F gene during development reduces hippocampal cell numbers of GABA+, Parv+, and NPY+ neurons, GABAergic synapses, increases mTOR signaling, and increases seizure susceptibility. The Sema 3F genetic lesion is duplicated by postnatal exposure to methylmercury. Conclusions: These studies support our hypothesis that gene-environment interactions with the transcriptional regulatory network of Sema 3F signaling and the mTOR pathway contributes to the placement of interneurons within hippocampal GABAergic circuitry and subsequent neuronal excitability. Supported by a PREP grant from the EFA and the Vanderbilt Center for Molecular Toxicology