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

Nat Commun. 2024 Jun 10;15(1):4945. doi: 10.1038/s41467-024-48257-6.

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.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Basolateral Nuclear Complex / drug effects
  • Basolateral Nuclear Complex / metabolism
  • Cell Polarity / drug effects
  • Corticosterone
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / metabolism
  • Disease Models, Animal*
  • Glutamic Acid / metabolism
  • Humans
  • Ketamine* / pharmacology
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons* / drug effects
  • Neurons* / metabolism
  • Prefrontal Cortex* / drug effects
  • Prefrontal Cortex* / metabolism
  • Stress, Psychological
  • Synapses* / drug effects
  • Synapses* / metabolism

Substances

  • Ketamine
  • Corticosterone
  • LIM Domain Proteins
  • Glutamic Acid
  • Antidepressive Agents