Acute alcohol and chronic drinking bidirectionally regulate the excitability of prefrontal cortex vasoactive intestinal peptide interneurons.

The prefrontal cortex (PFC) regulates drinking behaviors and affective changes following chronic alcohol use. PFC activity is dynamically modulated by local inhibitory interneurons (INs), which can be divided into non-overlapping groups with distinct functional roles. Within deeper layers of neocortex, INs that express either parvalbumin or somatostatin directly inhibit pyramidal cells. By contrast, the plurality of all remaining INs express vasoactive intestinal peptide (VIP), reside within superficial layers, and preferentially target other types of INs. While recent studies have described adaptations to PFC parvalbumin-INs and somatostatin-INs in alcohol use models, whether ethanol or drinking affect the physiology of PFC VIP-INs has not been reported. To address this gap, we used genetically engineered female and male mice to target VIP-INs in layers 1-3 of prelimbic PFC for whole-cell patch-clamp electrophysiology. We found that ethanol (20 mM, ∼0.09 BEC/90 mg/dL) application to PFC brain slices enhances VIP-IN excitability. We next examined effects following chronic drinking by providing mice with 4 weeks of intermittent access (IA) ethanol two-bottle choice in the home cage. In these studies, VIP-INs from female and male IA ethanol mice displayed reduced excitability relative to cells from water-only controls. Finally, we assessed whether these effects continue into abstinence. After 7-13 days without ethanol, the hypo-excitability of VIP-INs from male IA ethanol mice persisted, whereas cells from female IA ethanol mice were not different from their controls. Together, these findings illustrate that acute ethanol enhances VIP-IN excitability and suggest these cells undergo pronounced homeostatic changes following long-term drinking.

GPCR interactions involving metabotropic glutamate receptors and their relevance to the pathophysiology and treatment of CNS disorders.

Cellular responses to metabotropic glutamate (mGlu) receptor activation are shaped by mechanisms of receptor-receptor interaction. mGlu receptor subtypes form homodimers, intra- or inter-group heterodimers, and heteromeric complexes with other G protein-coupled receptors (GPCRs). In addition, mGlu receptors may functionally interact with other receptors through the ßγ subunits released from G proteins in response to receptor activation or other mechanisms. Here, we discuss the interactions between (i) mGlu1 and GABAB receptors in cerebellar Purkinje cells; (ii) mGlu2 and 5-HT2Aserotonergic receptors in the prefrontal cortex; (iii) mGlu5 and A2A receptors or mGlu5 and D1 dopamine receptors in medium spiny projection neurons of the indirect and direct pathways of the basal ganglia motor circuit; (iv) mGlu5 and A2A receptors in relation to the pathophysiology of Alzheimer's disease; and (v) mGlu7 and A1 adenosine or α- or ß1 adrenergic receptors. In addition, we describe in detail a novel form of non-heterodimeric interaction between mGlu3 and mGlu5 receptors, which appears to be critically involved in mechanisms of activity-dependent synaptic plasticity in the prefrontal cortex and hippocampus. Finally, we highlight the potential implication of these interactions in the pathophysiology and treatment of cerebellar disorders, schizophrenia, Alzheimer's disease, Parkinson's disease, l-DOPA-induced dyskinesias, stress-related disorders, and cognitive dysfunctions. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".

Sex differences and hormonal regulation of metabotropic glutamate receptor synaptic plasticity.

Striking sex differences exist in presentation and incidence of several psychiatric disorders. For example, major depressive disorder is more prevalent in women than men, and women who develop alcohol use disorder progress through drinking milestones more rapidly than men. With regards to psychiatric treatment responses, women respond more favorably to selective serotonin reuptake inhibitors than men, whereas men have better outcomes when prescribed tricyclic antidepressants. Despite such well-documented biases in incidence, presentation, and treatment response, sex as a biological variable has long been neglected in preclinical and clinical research. An emerging family of druggable targets for psychiatric diseases, metabotropic glutamate (mGlu) receptors are G-protein coupled receptors broadly distributed throughout the central nervous system. mGlu receptors confer diverse neuromodulatory actions of glutamate at the levels of synaptic plasticity, neuronal excitability, and gene transcription. In this chapter, we summarize the current preclinical and clinical evidence for sex differences in mGlu receptor function. We first highlight basal sex differences in mGlu receptor expression and function and proceed to describe how gonadal hormones, notably estradiol, regulate mGlu receptor signaling. We then describe sex-specific mechanisms by which mGlu receptors differentially modulate synaptic plasticity and behavior in basal states and models relevant for disease. Finally, we discuss human research findings and highlight areas in need of further research. Taken together, this review emphasizes how mGlu receptor function and expression can differ across sex. Gaining a more complete understanding of how sex differences in mGlu receptor function contribute to psychiatric diseases will be critical in the development of novel therapeutics that are effective in all individuals.

Modeling intrahippocampal effects of anterior hippocampal hyperactivity relevant to schizophrenia using chemogenetic excitation of long axis-projecting mossy cells in the mouse dentate gyrus.

BACKGROUND: The anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive, as is the ventral hippocampus in many rodent models for schizophrenia risk. Mossy cells (MCs) of the ventral dentate gyrus (DG) densely project in the hippocampal long axis, targeting both dorsal DG granule cells and inhibitory interneurons. Mossy cells are responsive to stimulation throughout hippocampal subfields, and thus may be suited to detect hyperactivity in areas where it originates such as CA1. Here we tested the hypothesis that hyperactivation of ventral MCs activates dorsal DG granule cells to influence dorsal hippocampal function. METHODS: In CD-1 mice, we targeted dorsal DG-projecting ventral MCs using an adeno-associated virus intersectional strategy. In vivo fiber photometry recording of ventral MCs was performed during exploratory behaviors. We used excitatory chemogenetic constructs to test the effects of ventral MC hyperactivation on long-term spatial memory during an object location memory task. RESULTS: Photometry revealed ventral MCs were activated during exploratory rearing. Ventral MCs made functional monosynaptic inputs to dorsal DG granule cells, and chemogenetic activation of ventral MCs modestly increased activity of dorsal DG granule cells measured by c-Fos. Finally, chemogenetic activation of ventral MCs during the training phase of an object location memory task impaired test performance 24 hours later, without effects on locomotion or object exploration. CONCLUSIONS: These data suggest that ventral MC activation can directly excite dorsal granule cells and interfere with dorsal DG function, supporting future study of their in vivo activity in animal models for schizophrenia featuring ventral hyperactivity.

mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.

Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system.

mGlu5 receptors are involved in mechanisms of activity-dependent synaptic plasticity, and are targeted by drugs developed for the treatment of CNS disorders. We report that mGlu3 receptors, which are traditionally linked to the control of neurotransmitter release, support mGlu5 receptor signaling in neurons and largely contribute to the robust mGlu5 receptor-mediated polyphosphoinositide hydrolysis in the early postnatal life. In cortical pyramidal neurons, mGlu3 receptor activation potentiated mGlu5 receptor-mediated somatic Ca2+ mobilization, and mGlu3 receptor-mediated long-term depression in the prefrontal cortex required the endogenous activation of mGlu5 receptors. The interaction between mGlu3 and mGlu5 receptors was also relevant to mechanisms of neuronal toxicity, with mGlu3 receptors shaping the influence of mGlu5 receptors on excitotoxic neuronal death. These findings shed new light into the complex role played by mGlu receptors in physiology and pathology, and suggest reconsideration of some of the current dogmas in the mGlu receptor field.

GluN1 deletions in D1- and A2A-expressing cell types reveal distinct modes of behavioral regulation.

N-methyl-d-aspartate receptors (NMDARs) are profound regulators of glutamate neurotransmission and behavior. To coordinate components of the limbic system, the dorsal and ventral striatum integrate cognitive and emotional information towards the execution of complex behaviors. Striatal outflow is conveyed by medium spiny neurons (MSNs), which can be dichotomized by expression of dopamine receptor subtype 1 (D1) or adenosine receptor subtype 2A (A2A). To examine how striatal NMDAR function modulates reward-related behaviors, we generated D1- and A2A-specific genetic deletions of the obligatory GluN1 subunit. Interestingly, we observed no differences in any GluN1-/- genotype in reward learning as assessed by acquisition or extinction of cocaine conditioned place preference (CPP). Control and A2A-GluN-/- mice exhibited robust cocaine-primed reinstatement, however this behavior was markedly absent in D1-GluN-/- mice. Interestingly, dual D1-/A2A-GluN-/- mice displayed an intermediate reinstatement phenotype. Next, we examined models of exploration, anxiety, and despair, states often associated with relapse to addiction-related behavior, to determine NMDAR contribution in D1 and A2A cell types to these behaviors. D1-GluN1-/- mice displayed aberrant exploratory locomotion in a novel environment, but the phenotype was absent in dual D1/A2A-GluN1-/- mice. In contrast A2A-GluN1-/- mice displayed a despair-resistant phenotype, and this phenotype persisted in dual D1/A2A-GluN-/- mice. These data support the hypothesis that cell type-specific NMDAR signaling regulates separable behavioral outcomes related to locomotion, despair, and relapse. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.