Metabotropic glutamate receptor signaling under physiological and pathophysiological conditions

PROJECT SUMMARY Group III metabotropic glutamate receptors (mGlu4/ 7/ 8) have emerged as targets for modulating glutamatergic synaptic transmission and plasticity in the brain areas implicated in schizophrenia and for regulating various symptoms associated with schizophrenia. Further, emerging literature suggests that polymorphisms in genes encoding for mGlu4 and mGlu7 are associated with increased risk of a schizophrenia diagnosis and may predict improvement in symptoms after treatment with antipsychotics. However, the circuit-specific mechanisms by which activation of these receptors can affect schizophrenia-like physiological and behavioral deficits in rodent models relevant to schizophrenia are not clear. We present extensive data that a novel agonist of mGlu4/7 receptors, LSP2-9166, decreases excitatory neurotransmission at synapses from thalamic (TH), but not basolateral amygdala (BLA), afferents to dopamine receptor 1 expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc). LSP2-9166 also corrects phencyclidine- (PCP, which causes pathophysiological changes and behavioral disturbances relevant to schizophrenia in rodents)-induced increases in glutamatergic neurotransmission at TH-D1-MSN synapses in the NAc. These novel findings provide mechanistic insights into gene polymorphism studies showing associations between mutations in gene encoding for mGlu4/7 receptors and risk for developing schizophrenia and suggest that agents modulating mGlu4/7 signaling may provide symptomatic relief in schizophrenia patients. We will now use selective negative allosteric modulators of mGlu4 and mGlu7, as well as optogenetic approaches, to modulate the activity of specific neuronal populations to test the proposed aims. In specific aim 1, we will use LSP2-9166, either alone or in the presence of selective pharmacological tools to test the hypothesis that LSP2-9166 acts at mGlu4/7 and selectively reduces glutamatergic neurotransmission from thalamic afferents in the NAc. In specific aims 2 and 3, we will directly test the hypothesis that activation of mGlu4/7 will normalize abnormally high glutamatergic signaling through thalamic afferents in the NAc and rescue sociability deficits in mice treated with PCP during juvenile development. These results will provide important information about the function of mGlu3 in brain circuits relevant to schizophrenia and will guide discovery efforts to develop highly selective modulators targeting either mGlu4 or mGlu7 receptors as novel therapeutics for treating behavioral deficits in schizophrenia.