Ketamine’s rapid antidepressant effects are mediated by Ca²⁺-permeable AMPA receptors in the hippocampus

Abstract

Ketamine is shown to enhance excitatory synaptic drive in the hippocampus, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamines therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that inhibits excitatory synaptic transmission and postsynaptic Ca2+ signaling. Thus, it is a puzzling question how ketamine enhances glutamatergic and Ca2+ activity in neurons to induce rapid antidepressant effects while blocking NMDARs in the hippocampus. Here, we find that ketamine treatment for one hour in cultured mouse hippocampal neurons significantly reduces calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately induces the expression of Ca2+ - permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). Such ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and synaptic plasticity in cultured hippocampal neurons. When a sub-anesthetic dose of ketamine is given to mice, it increases synaptic GluA1 levels, but not GluA2, and GluA1 phosphorylation in the hippocampus within one hour after treatment. These changes are likely mediated by ketamine-induced reduction of calcineurin activity in the hippocampus. Using the open field and tail suspension tests, we demonstrate that a low dose of ketamine rapidly reduces anxiety-like and depression-like behaviors in both male and female mice. However, when in vivo treatment of a CP-AMPAR antagonist abolishes the ketamines effects on animals behavior. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity in the hippocampus, which in turn enhances synaptic strength to induce rapid antidepressant actions.

Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer’s disease

“…We further determined how Aβ affected neuronal activity in PV+ and SST+ interneurons. As somatic Ca 2+ levels in neurons indicate neuronal activity 59 , we measured spontaneous somatic Ca 2+ activity without tetrodotoxin (TTX) in 12-14 DIV cultured hippocampal neurons as carried out previously 35,36,60,61 . 250 nM oAβ42 treatment significantly decreased neuronal activity in both PV+ and SST+ interneurons (PV+ cells; sAβ42, 1.000 ± 0.379 ΔF/F min and oAβ42, 0.589 ± 0.223 ΔF/F min , p = 0.0371 and SST+ cells; sAβ42, 1.000 ± 0.500 ΔF/F min and oAβ42, 0.650 ± 0.330 ΔF/F min , p = 0.0206) (Fig.…”

“…To do this, we used AAV to express Cre-dependent GCaMP7s (Addgene# 104495-AAV1) 135 in cells prepared from PV-Cre or SST-Cre mice. We then measured Ca 2+ activity in the soma of 14 DIV cultured hippocampal excitatory neurons with a modification of the previously described method 35,36,60,61,[137][138][139] . For GCaMP7s, the images were captured right after 250 nM sAβ42 or 250 nM oAβ42 was added to the media in the presence or absence of each agonist.…”

The autism-associated loss of δ-catenin functions disrupts social behaviors

“…We carried out Ca 2+ imaging with glutamate uncaging in cultured mouse cortical neurons to determine glutamatergic activity as described previously (121). For Ca 2+ imaging, a genetically encoded Ca 2+ indicator, GCaMP, was used.…”