Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus.

Alteration in the inhibitory and excitatory synaptic transmission (I/E) balance is a fundamental principle underlying the circuit dysfunction observed in many neuropsychiatric and neurodevelopmental disorders. The I/E ratio is dynamic, continuously changing because of synaptic short-term plasticity. We show here that transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, causes frequency-dependent alterations in the I/E ratio and in circuit function in hippocampus. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α-deficient) mice have enhanced inhibition in CA1, the opposite of what is seen in cortex. This study fills an important gap in current understanding of how changes in inhibition in complex brain disorders affect I/E dynamics, leading to region-specific circuit dysfunction and behavioral impairment. This study also provides a conceptual framework for analyzing the effects of short-term plasticity on the I/E balance in disease models.