Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Farhan Ali, Danielle M. Gerhard, Katherine Sweasy, Santosh Pothula, Christopher Pittenger, Ronald S. Duman and Alex C. Kwan ()
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Farhan Ali: Yale University School of Medicine
Danielle M. Gerhard: Yale University School of Medicine
Katherine Sweasy: Yale University School of Medicine
Santosh Pothula: Yale University School of Medicine
Christopher Pittenger: Yale University School of Medicine
Ronald S. Duman: Yale University School of Medicine
Alex C. Kwan: Yale University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.

Date: 2020
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DOI: 10.1038/s41467-019-13809-8

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