Optopharmacological studies of presynaptic metabotropic glutamate receptor 2 in corticolimbic circuits

点击翻译按钮获取中文摘要

ABSTRACT Psychiatric disorders are extremely common throughout the human population and remain among the most expensive and difficult illnesses to treat. Psychiatric disorders consist of many types of conditions, including forms of anxiety and depression, which have many overlapping symptoms, including cognitive deficits. In order to identify new drug targets to treat these disorders, research has shifted beyond serotonergic and dopaminergic drugs, and has recently focused on targeting the glutamatergic system in the brain. Glutamate is the most abundant neurotransmitter in the brain, and plays a critical role in maintaining neurological homeostasis. A major cause of psychiatric disorders is stress, which can affect glutamatergic signaling in numerous ways. For these reasons, glutamate receptors are being evaluated as mediators of disease pathophysiology and as potential treatment targets. Specifically, metabotropic glutamate receptors (mGluRs) are G protein-coupled recepetors (GPCRs) which play a neuromodulatory role in sensing and regulating glutamate release at the synapse. Preclinical and clinical trials targeting mGluR2 and mGluR3, inhibitory Gi/o-coupled mGluRs, have shown some promise in reducing anxiety. However, other trials have failed or had mixed results, indicating that a more precise dissection of the role of mGluRs in the neurophysiology of psychiatric disorders is needed. mGluR2 is a unique target at glutamate synapses due to its predominant expression as a presynaptic autoreceptor, where it inhibits glutamate release and, following prolonged activation, can causes long-term changes in synaptic strength. Importantly, mGluR2 is highly expressed in the medial prefrontal cortex (mPFC) and the basolatoral amygdala (BLA), key regions that regulate both mood and cognition. Disruption in the mPFC-BLA corticolimbic circuit plays a key role in psychiatric disorders, and many human studies indicate connectivity between these brain regions is disrupted in psychiatric patients. Some studies indicate that mGluR2 plays a critical role in regulating neuronal activity in the mPFC and BLA, but the underlying mechanisms are unclear. Current pharmacological methods cannot distinguish between mGluR2 and mGluR3, and do not provide spatial, temporal, or cell type-specific targeting in order to elucidate the function of specific mGluR2 sub-populations in the brain. This proposal aims to use new optogenetic techniques to address current gaps in the understanding of the expression, signaling, and behavioral changes elicited by presynaptic mGluR2 within the mPFC–BLA circuit in a stress-induced rodent model of mood disorders.