GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Abstract

R e s e a R c h a R t i c l e2 4 8 2 jci.org Volume 126 Number 7 July 2016 IntroductionMajor depressive disorder (MDD) is a recurring neuropsychiatric illness that affects up to 17% of the population and causes substantial social and economic burdens (1-4). While some patients respond to existing medications, currently available antidepressants take weeks to months to have an effect, and many patients are considered treatment resistant because they fail to respond to 2 or more antidepressants (5). Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6-8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9-11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12-19). However, a major question in the field is, what are the initial cellular targets that mediate the increase in glutamate transmission, leading to increased synapse formation and rapid antidepressant behavior (10, 20, 21)? One hypothesis is that scopolamine blocks muscarinic receptors on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and increased glutamate transmission. Alternatively, scopolamine may act directly on pyramidal neurons to enhance synaptic plasticity and produce antidepressant behavioral responses. Recent studies suggest that the M1-type muscarinic ACh receptor (M1-AChR) subtype may mediate the antidepressant actions of scopolamine (9, 22, 23).M1-AChRs are expressed on both GABAergic interneurons and glutamatergic pyramidal neurons in the mPFC and regulate the activity of both cell types (24)(25)(26).In the present study, we used transgenic mice and viralmediated gene transfer to drive Cre-dependent expression of M1-AChR shRNA in different subtypes of GABA interneurons or glutamate neurons in the mPFC. The results demonstrate that M1-AChR knockdown in GABA interneurons, but not pyramidal neurons, blocks the antidepressant-like response to scopolamine in mouse behavioral models. In addition, we show that knockdown of M1-AChR in somatostatin (SST), but not parvalbumin (PV), interneurons, blocks the actions of scopolamine. These findings reveal that M1-AChRs on SST interneurons in the mPFC are a critical cellular target underlying the rapid antidepressant effects of scopolamine. Results CaMKII+ and GAD + cell type-specific knockdown of M1-AChR in the mPFC. To determine whether glutamatergic pyramidal neurons and GABAergic interneurons in the mPFC express M1-AChR, double immunohistology was conducted with an M1-AChR antibody and Ca 2+ /calmodulin-dependent kinase II (CaMKII; pyramidal cell) or glutamate decarboxylase-67 (GAD67; GABA interneuron) (25). The results show that CaMKII + pyramidal neurons display punctate M1-AChR labeling in the mPF...

Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants

“…These symptoms are treated, to varying degrees, with antidepressant drugs [37,38], second-generation antipsychotics including clozapine and olanzapine [39,40,41], and muscarinic antagonists [42,43]. The same drugs have been used to reduce immobility times in the forced swimming test [20,44,45,46], and, as shown here, they significantly reduce immobility in C. elegans .…”

“…Intriguingly, cyproheptadine, ritanserin, metergoline, and scopolamine have all been reported to treat depression [42,43,58,59,60,61], whereas atropine has antidepressant effects in the forced swimming test [20]. There is a notable connection between muscarinic activity and insulin, not only in our system but also involving insulin regulation of muscarinic signaling in GABAergic neurons of the prefrontal cortex [62] - a site of scopolamine's antidepressant action [43]. …”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…In rodents, scopolamine administration resulted in rapid antidepressant actions in the 24-h forced-swim test [81, 82], learned helplessness [83, 84], novelty-suppressed feeding paradigm [81, 82] and attenuated chronic stress-induced deficits in sucrose preference [81] (see Table 1). These antidepressant effects in animal models were shown to be mediated by the effects of scopolamine to block the M1 subtype of mAChRs [81, 85], however, some evidence for M2 mAChR blockade as the mediator of these effects of scopolamine in animal models also exists [86].…”

“…Activation of M1-mAChRs expressed on GABAergic interneurons was shown to result in rapid excitation of interneuron activity and thus reinforcing an inhibitory input to the pyramidal neurons [158–160]. M1-mAChR knockdown specifically in somatostatin positive GABAergic interneurons, but not parvalbumin interneurons or pyramidal neurons, prevents the antidepressant behavioral actions of scopolamine [82]. Together, these findings indicate that inhibition M1-mAChR on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and enhancement of glutamatergic transmission may be involved in the rapid antidepressant actions of scopolamine.…”

New Insight Into the Mechanisms of Fast-Acting Antidepressants: What We Learn From Scopolamine

“…Ketamine’s noncompetitive antagonism at the NMDAR on inhibitory gamma-aminobutyric acidergic (GABAergic) interneurons in the PFC results in decreased GABA release and subsequent disinhibition of glutamatergic neurons (7). This “burst” in glutamate release then activates alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and L-type voltage-dependent calcium channels on the postsynaptic membrane, leading to increased firing of the postsynaptic neuron and the activity-dependent release of BDNF.…”