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Graphical AbstractHighlights d ChI activity is decreased in NAc shell in mouse models of depression d Inhibition of ChIs renders naive mice susceptible to stress d Dysfunction of HCN2 channels underlies reduced ChI activity in depressive mice d Enhancing ChI activity by chemogenetics or HCN2 overexpression rescues depression Correspondence ysagi@rockefeller.edu (Y.S.), greengard@rockefeller.edu (P.G.) In Brief Cheng et al. show that decreased expression and function of HCN2 channels cause reduced ChI tonic activity in NAc shell that leads to depressive phenotypes. Targeting HCN2 channels to enhance ChI activity is sufficient to rescue depression. SUMMARYCholinergic interneurons (ChIs) in the nucleus accumbens (NAc) have been implicated in drug addiction, reward, and mood disorders. However, the physiological role of ChIs in depression has not been characterized. Here, we show that the tonic firing rate of ChIs in NAc shell is reduced in chronic stress mouse models and in a genetic mouse model of depression. Chemogenetic inhibition of NAc ChIs renders naive mice susceptible to stress, whereas enhancement of ChI activity reverses depressive phenotypes. As a component of the molecular mechanism, we found that the expression and function of the hyperpolarization-activated cyclic nucleotidegated channel 2 (HCN2) are decreased in ChIs of NAc shell in depressed mice. Overexpression of HCN2 channels in ChIs enhances cell activity and is sufficient to rescue depressive phenotypes. These data suggest that enhancement of HCN2 channel activity in NAc ChIs is a feasible approach for the development of a new class of antidepressants.Detailed methods are provided in the online version of this paper and include the following:TABLE d CONTACT FOR REAGENT AND RESOURCE SHARING d EXPERIMENTAL MODEL AND SUBJECT DETAILS B Mice d METHOD DETAILS B NAc slice preparation and electrophysiology B Stereotaxic surgery B Behavioral assays B Chronic SDS B Chronic restraint stress B SSDS B SPT B SA test B Open field test B Forced swim test B Tail suspension test B Immunohistochemistry B RNA-seq of TRAP samples B Biostatistics B Semiquantitative PCR B Virus generation d QUANTIFICATION AND STATISTICAL ANALYSIS d DATA AND SOFTWARE AVAILABILITY SUPPLEMENTAL INFORMATION Supplemental Information includes six figures and two tables and can be found with this article online at https://doi.org/10.1016/j.neuron.2018.12.018. ACKNOWLEDGMENTSWe would like to thank J. Gresack for suggestions on behavioral studies, J. Zhang for biostatistical analysis, L. Medrihan for discussions on electrophysiology, J. Chang and T. Liebmann for their suggestions on the immunohistochemistry, E. Griggs for assistance with the graphic preparation, K. George and S. Reed for mouse line maintenance, and B. Labonté for instructions on SDS model.

We have recently shown that the anti-Parkinson-propargylcontaining monoamine oxidase B (MAO-B) inhibitor drug, rasagiline [N-propargyl-(1R)-aminoindan], and its cholinesterase inhibitor derivatives TV3326 and TV3279, regulate amyloid precursor protein (APP) processing by a protein kinase C (PKC)-dependent mechanism in SH-SY5Y neuroblastoma and PC12 cells. In the present study, we investigated the effect of rasagiline and its derivatives on the regulation of the PKC-dependent mechanism and APP processing under in vivo conditions. Administration of rasagiline (0.1 mg/kg) to male C57/BL mice for 14 days significantly decreased membrane-bound holoprotein APP levels in the hippocampus. Additionally, we observed that rasagiline up-regulated p-PKC levels and the expression of a and e PKC isozymes in the hippocampus, indicating that the mechanism by which rasagiline affects APP processing may be related to PKC-associated signalling. The results also demonstrate that rasagiline treatment significantly elevated the levels of phosphorylated myristoylated alanine-rich C kinase substrate (p-MARCKS), a major substrate for PKC, as well as the levels of receptors for activated C kinase 1 (RACK1). Similar effects on APP and PKC levels were also demonstrated for the two cholinesterase inhibitor derivatives of rasagiline, TV3326 and TV3279. These results indicate that rasagiline and its derivatives regulate PKC-dependent mechanisms and APP processing. The activation and induction of PKC and MARCKS by these drugs may have a crucial role not only in their neuroprotective activity, but also in their ability to affect neuronal plasticity and spatial learning processes. Keywords: amyloid precursor protein, myristoylated alaninerich C kinase substrate, protein kinase C, rasagiline.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressant drugs, but the cellular and molecular mechanisms by which their therapeutic action is initiated are poorly understood. Here we show that serotonin 5-HT1B receptors in cholecystokinin (CCK) inhibitory interneurons of the mammalian dentate gyrus (DG) initiate the therapeutic response to antidepressants. In these neurons, 5-HT1B receptors are expressed presynaptically, and their activation inhibits GABA release. Inhibition of GABA release from CCK neurons disinhibits parvalbumin (PV) interneurons and, as a consequence, reduces the neuronal activity of the granule cells. Finally, inhibition of CCK neurons mimics the antidepressant behavioral effects of SSRIs, suggesting that these cells may represent a novel cellular target for the development of fast-acting antidepressant drugs.

The behavioral response to antidepressants is closely associated with physiological changes in the function of neurons in the hippocampal dentate gyrus (DG). Parvalbumin interneurons are a major class of GABAergic neurons, essential for DG function, and are involved in the pathophysiology of several neuropsychiatric disorders. However, little is known about the role(s) of these neurons in major depressive disorder or in mediating the delayed behavioral response to antidepressants. Here we show, in mice, that hippocampal parvalbumin interneurons express functionally silent serotonin 5A receptors, which translocate to the cell membrane and become active upon chronic, but not acute, treatment with a selective serotonin reuptake inhibitor (SSRI). Activation of these serotonergic receptors in these neurons initiates a signaling cascade through which Gi-protein reduces cAMP levels and attenuates protein kinase A and protein phosphatase 2A activities. This results in increased phosphorylation and inhibition of Kv3.1β channels, and thereby reduces the firing of the parvalbumin neurons. Through the loss of this signaling pathway in these neurons, conditional deletion of the serotonin 5A receptor leads to the loss of the physiological and behavioral responses to chronic antidepressants.

Little is known about the molecular similarities and differences between neurons in the ventral (vSt) and dorsal striatum (dSt) and their physiological implications. In the vSt, serotonin [5-Hydroxytryptamine (5-HT)] modulates mood control and pleasure response, whereas in the dSt, 5-HT regulates motor behavior. Here we show that, in mice, 5-HT depolarizes cholinergic interneurons (ChIs) of the dSt whereas hyperpolarizing ChIs from the vSt by acting on different 5-HT receptor isoforms. In the vSt, 5-HT1A (a postsynaptic receptor) and 5-HT1B (a presynaptic receptor) are highly expressed, and synergistically inhibit the excitability of ChIs. The inhibitory modulation by 5-HT1B, but not that by 5-HT1A, is mediated by p11, a protein associated with major depressive disorder. Specific deletion of 5-HT1B from cholinergic neurons results in impaired inhibition of ACh release in the vSt and in anhedonic-like behavior.5-HT1A | 5-HT1B | cholinergic interneurons | ventral striatum | TRAP C holinergic interneurons (ChIs) represent only 1-2% of all striatal neurons (1). Despite their low abundance, ChIs play a major role in striatal function, by modulating both inputs to and outputs from spiny projection neurons (SPNs) (2). In the ventral striatum (vSt), ChIs are thought to play a major role in mediating reward, motivation, food intake, and hedonic behavior, whereas ChIs of the dorsal striatum (dSt) are implicated in motor behavior and action selection (3-5). Despite their functional differences, only a few morphological differences between vSt and dSt ChIs have been demonstrated, but no molecular differences between these two populations have been reported (6).Serotonin [5-Hydroxytryptamine (5-HT)] signaling in the striatum has long been implicated in modulating locomotion as well as in mood control (7-9). Striatal 5-HT levels are high, and multiple 5-HT receptors (5-HTRs) are thought to mediate the function of 5-HT in these circuits (7, 10). In dSt ChIs, several 5-HTRs (5-HT7, 5-HT6, and 5-HT2) have been reported to induce membrane depolarization (11,12), but the role of 5-HT signaling in vSt ChIs and its implication for mood regulation are poorly understood. To elucidate the role of 5-HT in vSt ChIs, we used electrophysiological recordings, optogenetics, and cell type-specific gene expression analysis. We demonstrate that 5-HT1A and 5-HT1B synergistically inhibit the function of vSt ChIs. The effect of activation of 5-HT1B, but not that of 5-HT1A, is mediated by p11. Furthermore, deletion of 5-HT1B from cholinergic neurons resulted in a loss of pleasure response (anhedonia), a core symptom of major depressive disorder. ResultsOpposite Effects of 5-HT on Cell Excitability Between vSt ChIs and dSt ChIs. To investigate the effect of 5-HT on ChIs from the vSt and dSt, we carried out electrophysiological recordings from visually identified neurons in acute brain slices. To identify ChIs, we used translating ribosome affinity purification (TRAP) mice expressing a GFP-tagged ribosomal protein, L10a, under the choline acetyltrans...

Abstract(R)-[(N-propargyl-(3R) aminoindan-5-yl) ethyl methyl carbamate] (TV3326) is a novel cholinesterase and brain-selective monoamine oxidase (MAO)-A/-B inhibitor. It was developed for the treatment of dementia co-morbid with extra pyramidal disorders (parkinsonism), and depression. On chronic treatment in mice it attenuated striatal dopamine depletion induced by MPTP and prevented the reduction in striatal tyrosine hydroxylase activity, like selective B and non-selective MAO inhibitors. TV3326 preferentially inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the prevention of MPTP-induced dopamine depletion. Complete inhibition of MAO-B is not necessary for full protection from MPTP neurotoxicity. Unlike that seen after treatment with other MAO-A and -B inhibitors, recovery of striatal and hippocampal MAO-A and -B activities from inhibition by TV3326 did not show first-order kinetics. This has been attributed to the generation of a number of metabolites by TV3326 that cause differential inhibition of these enzymes. Inhibition of brain MAO-A and -B by TV3326 resulted in significant elevations of dopamine, noradrenaline and serotonin in the striatum and hippocampus. This may explain its antidepressant-like activity, resembling that of moclobemide in the forced-swim test in rats.