Ketamine increases activity of anterior striatal projections that modulate compulsive behavior in SAPAP3 knockout mice

Davis, GL, Minerva, AR, Lario, A., et al. Ketamine increases activity of anterior striatal projections that modulate compulsive behavior in SAPAP3 knockout mice. nat commun 12, 6040 (2021). https://doi.org/10.1038/s41467-021-26247-2

Commentary

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions) and is associated with dysfunction of frontal striatal circuits.

However, there is no immediate pharmacological treatment for OCD.

Recent clinical studies have shown that intravenous infusion of ketamine rapidly reduces OCD symptoms. to scrutinize the mechanisms underlying the therapeutic effects of ketamine on OCD-like behaviors, we used the SAPAP3 knockout (KO) mouse model of compulsive grooming.

Here we summarize the fast-acting therapeutic effects of ketamine on compulsive behaviors and show that ketamine increases the activity of dorsal frontal lobe neurons that project to the dorsal striatum in KO mice.

Optogenetic mimicry of this increase in anterior striatal activity reduced compulsive grooming behavior in KO mice. Conversely, inhibition of this circuit in wild-type mice resulted in increased grooming. Finally, we show that ketamine blocks the worsening of grooming in KO mice caused by optogenetic inhibition of frontal striatal activity.

We show that ketamine increases activity in the anterior striatal circuit that causally regulates compulsive grooming behavior, suggesting that this circuit may be important for the therapeutic effects of ketamine in OCD.