GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

J Clin Invest. 2016 Jul 1;126(7):2482-94. doi: 10.1172/JCI85033. Epub 2016 Jun 6.

Abstract

Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MDD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined. Here, we demonstrate that the antidepressant-like effects of scopolamine are mediated by GABA interneurons in the medial prefrontal cortex (mPFC). Both GABAergic (GAD67+) interneurons and glutamatergic (CaMKII+) interneurons in the mPFC expressed M1-AChR. In mice, viral-mediated knockdown of M1-AChR specifically in GABAergic neurons, but not glutamatergic neurons, in the mPFC attenuated the antidepressant-like effects of scopolamine. Immunohistology and electrophysiology showed that somatostatin (SST) interneurons in the mPFC express M1-AChR at higher levels than parvalbumin interneurons. Moreover, knockdown of M1-AChR in SST interneurons in the mPFC demonstrated that M1-AChR expression in these neurons is required for the rapid antidepressant-like effects of scopolamine. These data indicate that SST interneurons in the mPFC are a promising pharmacological target for developing rapid-acting antidepressant therapies.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Anxiety / metabolism
  • Behavior, Animal
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Electrophysiology
  • Female
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • Humans
  • Interneurons / drug effects*
  • Interneurons / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Prefrontal Cortex / metabolism
  • Scopolamine / pharmacology*

Substances

  • Antidepressive Agents
  • Scopolamine