Dopamine system regulation of inhibition in an animal model of interneuron transcriptional dysregulation and hippocampal circuit dysfunction
Authors: Brady Lillian , Bartley Aundrea , Li Qin , Dobrunz Lynn 
Published: November 2023

Interneuron transcriptional dysregulation and hippocampal circuit dysfunction occur in many neuropsychiatric and neurodevelopmental disorders, including schizophrenia and autism. Parvalbumin (PV+) GABAergic interneurons, which are regulated by the transcriptional coactivator PGC‐1α, are important for controlling hippocampal network activity. Genetic deletion of PGC‐1α from mice results in decreased expression of PV in interneurons, which has also been consistently observed in postmortem tissue from schizophrenia patients. Our lab has previously shown that there is an increase in the inhibitory/excitatory (I/E) ratio at the Schaffer collateral – CA1 pathway in PGC‐1α−/− mice, which is caused by enhanced GABAergic inhibition. This leads to a reduction in the spread of activation in hippocampal CA1 as measured with voltage‐sensitive dye imaging. PGC‐1α−/− mice also have impaired nest building behavior and alterations in kainate‐induced gamma oscillations, indicating hippocampal circuit dysfunction. Dopamine (DA) has been shown to modulate GABAergic inhibitory synaptic transmission in hippocampus. Previously we found that haloperidol, a DA receptor antagonist with selectivity for D2‐like receptors, has different effects on synaptic transmission and circuit function in PGC‐1α−/− mice, suggesting that there are alterations in DA system regulation of inhibition. However, the effects of PGC‐1α deletion on the DA system are not fully understood. Here we use PGC‐1α−/− mice to investigate dysfunction in the interactions between the dopaminergic and GABAergic systems caused by interneuron transcriptional dysregulation. We find that DA has a disinhibitory effect on synaptic responses in both wildtype (WT) and PGC‐1α−/− slices, and there was no significant difference in the magnitude. There was also no difference in the effects of a D2 receptor antagonist. We next tested the effects of blocking DA D4 receptors, which are located on PV+ GABAergic interneurons in hippocampus, and are important for regulating gamma oscillations. Surprisingly, although blocking D4 receptors had no effect in WT slices, it increased the field potential in PGC‐1α−/− slices, an effect that was caused by disinhibition. The D4 receptor antagonist also restored baseline synaptic transmission and normalized hippocampal gamma oscillations as well as nest construction ability in PGC‐1α−/− mice. These data suggest that there is a tonic effect of D4 activation to enhance feed forward inhibition in PGC‐1α−/− slices, which causes the enhanced I/E ratio in these mice. Alterations in the DA system's modulation of inhibition, through changes in D4 receptor effects, are involved in the circuit dysfunction caused by deletion of PGC‐1α. The results from this study may lead to a greater understanding of circuit dysfunction in disorders of I/E imbalance, as well as provide information for the development of alternate pharmacotherapeutic approaches to restore I/E balance.

Support or Funding Information

NIH R01 MH098534 and UAB Cognition and Cognitive Disorders T‐32 Training Grant