T40. GPR52 AGONISTS REPRESENT A NOVEL APPROACH TO TREAT UNMET MEDICAL NEED IN SCHIZOPHRENIA

Abstract

s for the Sixth Biennial SIRS Conference S128 Poster Session I therapeutics mainly target the positive symptoms, cognitive symptoms are often not effectively treated. Our recent discovery that mGlu3 and mGlu5 can act as signaling partners to modulate synaptic plasticity in the prefron-tal cortex led us to hypothesize that mGlu3 may subserve similar functions to those of mGlu5 during hippocampal synaptic plasticity and hippocam-pal-dependent behaviors. Methods: We directly tested this hypothesis using acute slice electrophysiol-ogy to investigate basal synaptic transmission as well as long-term plasticity in hippocampal slices. To test cognition, the associative fear learning behavioral assay, termed trace-fear conditioning, was used. C57bl/6 mice or CaMKII-cre;mGlu5-/-mice were used in all studies. Results: We report that mGlu2/3 activation enhances hippocampal theta-burst (TBS)-induced LTP but was without effect on group I mGlu agonist-induced LTD The group II mGlu agonist enhancement of TBS-LTP was blocked by antagonists of mGlu3 or mGlu5. We next tested downstream mechanisms of group II mGlu induced LTP by chemically activating LTP with the group II agonist LY379268 in combination with selective antagonists. We verified the LTP was induced by mGlu3 activation but not mGlu2 using selective negative allosteric modulators of each subtype. Furthermore, mGlu5 negative allosteric modulation with MTEP blocked mGlu3-LTP, and conversely the mGlu5 positive allosteric modulator, VU0092273, enhanced mGlu3-LTP. The cannabinoid receptor type 1 antagonist AM251 was also capable of blocking mGlu3-LTP, suggesting cannabinoid signaling mechanistically drives this LTP. Having confirmed a role for mGlu5 in the mGlu3-LTP, we next verified that postsynaptic mGlu5 located on pyramidal neurons was necessary for mGlu3-LTP by utilizing CaMKII-cre;mGlu5-/-mice. It was found that hippocampal slices from these mice showed no enhancement of LTP when LY379268 was bath applied alone or in combination with TBS-stimulation. Behaviorally, we discovered that selective activation of mGlu3 by systemi-cally injecting the group II mGlu agonist in combination with a selective mGlu2 negative allosteric modulator, VU6001966, causes an enhancement in the acquisition of trace-fear conditioning learning. This was also confirmed to be dependent on mGlu5 as both systemic pharmacological inhibition or genetic deletion of mGlu5 abolished this learning enhancement. Further testing of the ability of mGlu3 activation to augment other cogni-tive tasks is currently underway. Discussion: These results taken together demonstrate mGlu3 enhances hip-pocampal LTP and hippocampal-dependent learning through mechanisms that involve both mGlu5 and CB1 receptor activation. This work provides a basic biological mechanism and preclinical therapeutic validation for mGlu3 as a target for neurological disorders in which cognition is disrupted such as schizophrenia. Background: There are currently no treatment options for key symptom domains in certain psychiatric and neurological diseases. For example, anti-psychotics effectively treat the positive symptoms of schizophrenia, however both the cognitive impairments associated with schizophrenia (CIAS) and negative symptoms, both key predictors of functional outcome, are not treated by current therapies. Additionally, psychotic symptoms associated with neurological diseases such as Alzheimer's Disease (AD) are not adequately treated with current antipsychotics. Therefore, novel mechanisms to address these unmet medical needs are urgently required and are under investigation. GPR52 is a Gs-coupled orphan g-protein coupled receptor which has an intriguing pattern of brain expression. In cortex, GPR52 is expressed