No abstract

No abstract

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.

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.

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.