Planar cell polarity proteins mediate ketamine-induced restoration of glutamatergic synapses in prefrontal cortical neurons in a mouse model for chronic stress.

A single low dose of ketamine produces both immediate and lasting antidepressant effects, linked to the repair of glutamatergic synapses in the medial prefrontal cortex. In a mouse model of chronic stress, ketamine altered multiple molecular pathways. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling decreased after chronic corticosterone treatment but increased after ketamine in most excitatory neurons. Similar PCP signaling reductions were predicted in the dorsolateral prefrontal cortex of people with major depressive disorder. Neurons connecting the infralimbic prefrontal cortex to the basolateral amygdala regulated immobility and food intake. Knocking out specific PCP proteins in these neurons blocked ketamine's synapse restoration and behavioral improvements, indicating that PCP proteins in this circuit mediate ketamine's effects.

Study at a glance

Abstract

Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.