Developmental Control of Cortical Gabaergic Interneuron Number Via Pten Signaling

Background:  GABA is the main inhibitory neurotransmitter in the mammalian nervous system. Proper balance of excitation and inhibition is critical for the normal development of cognition, as evidenced by a range of neuropsychiatric disorders, including autism spectrum disorder (ASD), that feature dysregulation of this process. Cortical GABAergic interneurons (INs) are over-produced during early development, with a substantial fraction undergoing programmed cell death through an unknown mechanism during early postnatal life to arrive at a mature population size. Pten encodes a phosphatase that regulates cell death under normal and pathological conditions, and mutations in PTEN are a risk factor for ASD.

Objectives:  In this study, we test the hypothesis that intrinsically determined cell death of developing cortical GABAergic INs occurs through a Pten-dependent mechanism.

Methods: We have generated mice in which a conditional heterozygous mutation in Pten is introduced into developing GABAergic cells. Our analysis of these mice has employed a variety of techniques, including immunohistochemistry, flow cytometry, cell culture and behavioral testing.

Results: We find that mutant animals fail to show the approximately 20% decrease in cortical GABAergic cells during early postnatal development that occurs in control animals. We also observe reduced markers of apoptosis in Pten mutant cortical GABAergic cells during development and we present evidence that Pten is both necessary and sufficient to induce the intrinsically determined cell death of this cell type. Mutant animals display increased seizure resistance, decreased social interaction, and altered cortical network activity as indicated by c-Fos, consistent with a net imbalance of excitation and inhibition.

Conclusions:  Together, our findings indicate a role for Pten in the intrinsic regulation of cell death and population size in developing cortical GABAergic INs. These results have relevance for understanding abnormal scaling of IN number in the brains of individuals with ASD.