Adult conditional knockout of PGC-1α in GABAergic neurons causes exaggerated startle reactivity, impaired short-term habituation and hyperactivity.

ABSTRACT

Interneurons not only contribute to the global balance of activity in cortical networks but also mediate the precise gating of information through specific proteins. Accumulating evidence demonstrates that peroxisome-proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1α) is concentrated in inhibitory interneurons and that it plays an important role in neuropsychiatric diseases. However, the functions of the transcriptional coactivator PGC-1α in sensorimotor gating, short-term habituation and spatial reference memory are still not entirely clear. To investigate the precise involvement of PGC-1α in the progression of psychiatric disorders, we first generated PGC-1α conditional knockout mice through transgenic expression of Cre recombinase under the control of dlx5/6 promoter, Cre-mediated excision events occurred specifically in γ-amino-butyric-acid-(GABA)ergic neurons. Short-term habituation and spatial reference memory in Dlx5/6-CrePGC-1αfl/fl mice were evaluated using the novel object recognition test and the Morris water maze test, and sensorimotor gating was measured by prepulse inhibition of the acoustic startle reflex. Protein expression of parvalbumin (PV) in specific brain regions was studied by western blotting, immunofluorescence and immunohistochemistry. Here, we show that mice lacking the PGC-1α gene in GABAergic neurons exhibit deficits in short-term habituation, hyperactivity, reduced prepulse inhibition and exaggerated startle reactivity but normal associative spatial reference memory. In particular, these mice display aberrant salience, whereby more attention is paid to a further copy of the original object (now familiar) (relative to the first presentation of the original object, and relative to the presentation of the novel object). These behavioral dysfunctions were associated with decreased PV expression in the cortex (including somatosensory and motor cortex) as well as in the hippocampus, especially in its CA1 and CA3 regions. Together, these findings draw attention to a hyper-response phenotype of PGC-1α conditional knockout mice and indicate that PGC-1α is a novel regulator of gene expression and function in PV-positive interneurons and a potential therapeutic target for psychiatric disorders associated with PGC-1α dysregulation.