Abstracts

Rationale: The PI3 kinase (PI3K) signaling pathway may mediate GABAergic interneuron migration and placement during neocortical development. PTEN is a potent regulatory protein controlling the rate of PI3K signaling through the mTOR pathway in neurons. Previous Cre deletion experiments with a floxed PTEN allele demonstrated neuronal deletion of PTEN led to epilepsy and autistic like behaviors in PTEN CKO mice. Methods: Classical molecular biological approaches along with cell specific ablation of PTEN signaling was used to test the hypothesis that cell specific PTEN signaling affects formation and function of GABAergic circuitry. Results: Cell specific ablation of PTEN in excitatory neurons or interneurons led to increased PTZ seizure susceptibility. Subsequent empirical analysis with mice homozygous null for PTEN in GABAergic neurons substantiated our predictions. Notably, deletion of PTEN in interneurons but not excitatory neurons during early development increased the number of interneurons and mRNAs for cell specific GABAergic markers. Deletion of PTEN signaling in either cell type during development regulated the mTOR pathway, providing a plausible explanation for the change in interneuron survival in adult animals. Conclusions: In conclusion, PTEN expression in developing interneurons is necessary but not sufficient for proper development of GABAergic circuitry. Such signaling pathways may have important implications for patients with the autism/epilepsy phenotype.