Lateral orbitofrontal dysfunction in the Sapap3 knockout mouse model of obsessive–compulsive disorder

Abstract

Obsessive–compulsive disorder (OCD) is a common psychiatric disorder that affects about 2% of the population, but the underlying neuropathophysiology of OCD is not well understood. Although increasing lines of evidence implicate dysfunction of the orbitofrontal cortex (OFC) in OCD, a detailed understanding of the functional alterations in different neuronal types in the OFC is still elusive. We investigated detailed activity pattern changes in putative pyramidal neurons and interneurons, as well as local field potential oscillations, in the lateral OFC underlying OCD-relevant phenotypes. We applied in vivo multichannel recording in an awake OCD mouse model that carried a deletion of the Sapap3 gene, and in wildtype littermates. Compared with wildtype mice, the lateral OFC of Sapap3 knockout mice exhibited network dysfunction, demonstrated by decreased power of local field potential oscillations. The activity of inhibitory and excitatory neurons in the lateral OFC showed distinct perturbations in Sapap3 knockout mice: putative interneurons exhibited increased activity; putative pyramidal neurons exhibited enhanced bursting activity; and both putative pyramidal neurons and interneurons exhibited enhanced discharge variability and altered synchronization. To exclude motor activity confounders, this study examined functional alterations in lateral OFC neurons only when the mice were stationary. We provide, to our knowledge, the first direct in vivo electrophysiological evidence of detailed functional alterations in different neuronal types in the lateral OFC of an OCD mouse model. These findings may help in understanding the underlying neuropathophysiology and circuitry mechanisms for phenotypes relevant to OCD, and may help generate and refine hypotheses about potential biomarkers for further investigation.