Because of the enormous impact of neuropsychiatric disorders on human health, and the scarcity of effective treatments, it is essential to advance the understanding of the synaptic and circuit mechanisms underlying neuropsychiatric disorders such as schizophrenia. Alteration in the balance of inhibition and excitation (I/E) is emerging as a fundamental unifying principle underlying a wide variety of complex brain disorders, including neuropsychiatric and neurodevelopmental disorders such as schizophrenia, bipolar disorder, autism, Down Syndrome, Rett Syndrome and Fragile X. I/E imbalance is often caused by alterations in GABAergic interneurons, particularly interneurons containing the calcium binding protein parvalbumin (PV). Transcriptional dysregulation in PV interneurons and GABAergic dysfunction are consistent finding in postmortem tissue of SZ patients. The effects of these changes on synaptic and circuit function are not well understood. In this proposal we will investigate alterations in the dynamic I/E balance in an animal model of inhibitory dysfunction caused by genetic deletion of PGC-1. PGC-1 (peroxisome proliferator activated receptor ? coactivator 1) is a transcriptional co-activator in interneurons that regulates transcription of P. Genetic deletion of PGC-1 in mice results in decreased expression of PV in interneurons and alterations in GABAergic inhibition. PGC-1 is therefore a potential mediator of the decreased PV seen in SZ. In addition, the gene for PGC-1 is associated with SZ and bipolar disorder. PGC-1-/- mice provide a way to investigate the multi-factorial effects on synaptic and circuit function of interneuron dysfunction cause by transcriptional dysregulation in interneurons. We will determine the mechanisms underlying the inhibitory dysfunction in PGC-1 deficient mice, as well as the overall effects on the dynamics of the I/E balance and on hippocampal circuit function. In addition, we will utilize pharmacological and optogenetic manipulation of the I/E balance as a means to restore the I/E balance in PGC-1 deficient mice, and determine the resulting effects on circuit function. The proposed studies will greatly advance our understanding of the effects of inhibitory dysfunction due to transcripitional dysregulation on the dynamics of I/E balance in hippocampus. This will provide insights into new strategies or therapeutic targets for correcting I/E imbalances, with implications for treatment of SZ and a wide range of other complex brain disorders involving I/E imbalance and circuit dysfunction.
The proposed studies will fill an important gap in the current knowledge of how transcriptional dysregulation in interneurons leads to circuit dysfunction. These studies may lead to new therapeutic strategies to correct the dynamic imbalance of inhibition and excitation in complex brain disorders such as schizophrenia.
