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

Abstract

Ketamine is shown to enhance excitatory synaptic drive in multiple brain areas, which is presumed to underlie its rapid antidepressant effects. Moreover, ketamine's therapeutic actions are likely mediated by enhancing neuronal Ca2+ signaling. However, ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist that reduces 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 in cultured mouse hippocampal neurons significantly reduces Ca2+ and calcineurin activity to elevate AMPA receptor (AMPAR) subunit GluA1 phosphorylation. This phosphorylation ultimately leads to the expression of Ca2+-Permeable, GluA2-lacking, and GluA1-containing AMPARs (CP-AMPARs). The ketamine-induced expression of CP-AMPARs enhances glutamatergic activity and glutamate receptor plasticity in cultured hippocampal neurons. Moreover, 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 ketamine's effects on animals' behaviors. We thus discover that ketamine at the low dose promotes the expression of CP-AMPARs via reduction of calcineurin activity, which in turn enhances synaptic strength to induce rapid antidepressant actions.

Nucleotide Contribution to the Functioning of SERT, Na<sup> </sup>/K<sup> </sup> ATPase and GPCR Proteins

“…Positron emission tomography measurements in monkeys following sub-lethal doses of ketamine identify transient inhibition of SERT activity [29]. Ketamine promotes plasticity in the hippocampus, via a negative synaptic feedback response expressed by a subtype of AMPA receptor [30]. Inhibition of NMDA receptors on GABAergic interneurons leads to disinhibition and activation of AMPA receptor pathways [31].…”

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates

“…The cortex, hippocampus, and remaining portions of the forebrain (forebrain) were isolated from P10 each pup prenatally exposed to VPA for whole cell lysate analysis. Additionally, we used whole brain tissues from VPA-treated pups and isolated the postsynaptic density (PSD) fraction as shown previously (Farooq et al, 2016; Kim et al, 2016; Kim et al, 2018; Kim, Titcombe, et al, 2015; Kim, Violette, et al, 2015; Mendez-Vazquez et al, 2023; Shou et al, 2018; Zaytseva et al, 2023). Brain tissues were rinsed with PBS, collected to 15 ml tubes, homogenized by douncing in solution A, and spun at 2000 rpm for 10 min at 4°C.…”

Brain region–specific action of ketamine as a rapid antidepressant

“…G iven ketamine's rapid and potent antidepressant activity and low addiction liability (1)(2)(3)(4), a challenge in neuroscience is to understand its direct brain target(s) at both the molecular and neural circuit levels. At the molecular level, a few key molecules that can mediate ketamine's effect have been identified, including brainderived neurotrophic factor (BDNF) (5,6), AMPAR (7)(8)(9), mammalian target of rapamycin (mTOR) (10), the potassium channel Kcnq2 (11), the translation initiation factor 4E-binding proteins (4E-BPs) (12), Menin (13), and microgliarelated inflammatory cytokines (14,15). However, because these molecules do not bind to ketamine, they cannot be its direct target and are most likely important downstream players in the signaling pathways.…”