Targeting mGlu5 and A(2A) receptors to attenuate sensorimotor gating deficits and restore homeostatic CREB signaling in a heritable rodent model of psychosis
Abstract
Individuals diagnosed with schizophrenia (SZ) suffer from impaired sensorimotor gating that contributes to cognitive disruption and the inability to filter out irrelevant sensory stimuli. The present study aims to address this deficit by targeting two receptors that have been implicated in the pathophysiology of SZ: the metabotropic glutamate receptor type 5 (mGlu5) and the adenosine 2A (A(2A)) receptor. Additionally, by stimulating these receptors we aim to attenuate increased cAMP response element-binding protein (CREB) levels that have been attributed to enhanced emotional reactivity in SZ. Enhanced dopamine D2 receptor sensitivity and signaling in the mesolimbic pathway of the brain are hallmarks of SZ. Therefore, in the present study we modeled D2 supersensitivity in Sprague-Dawley rats via neonatal injections of quinpirole (NQ) or saline (NS). NQ or NS-treated rats were bred together to produce an F1 generation of animals that exhibit phenotypes similar to that of NQ-treated parents. The F1 rats were tested on pre-pulse inhibition (PPI), a measure of sensorimotor gating, on post-natal days (P) 44-48. PPI has previously been used in clinical settings to screen antipsychotic medications. Prior to testing, rats received an injection of saline, mGlu5 positive allosteric modulator CDPPB (10 or 30 mg/kg), or A(2A) agonist CGS21680 (.03 or .09 mg/kg). On P50 brain tissue was harvested. The nucleus accumbens (NAc) was dissected from each subject and tissue was analyzed for CREB via enzyme-linked immunosorbent assay (ELISA). Results demonstrated that rats with at least one NQ-treated parent demonstrated PPI deficits that were generally alleviated by CDPPB or CGS21680, with dose-response changes across certain groups. In general, CGS21680 showed greater efficacy towards alleviation of PPI deficits. Both CDPPB and CGS21680 were successful in reducing CREB to control levels. Overall, the findings suggest that targeting mGlu5 or A(2A) receptors attenuates behavioral and proteomic abnormalities associated with psychosis.
Start Time
16-4-2025 9:00 AM
End Time
16-4-2025 11:30 AM
Presentation Type
Poster
Presentation Category
Health
Student Type
Graduate Student - Doctoral
Faculty Mentor
Russell Brown
Faculty Department
Biomedical Sciences
Targeting mGlu5 and A(2A) receptors to attenuate sensorimotor gating deficits and restore homeostatic CREB signaling in a heritable rodent model of psychosis
Individuals diagnosed with schizophrenia (SZ) suffer from impaired sensorimotor gating that contributes to cognitive disruption and the inability to filter out irrelevant sensory stimuli. The present study aims to address this deficit by targeting two receptors that have been implicated in the pathophysiology of SZ: the metabotropic glutamate receptor type 5 (mGlu5) and the adenosine 2A (A(2A)) receptor. Additionally, by stimulating these receptors we aim to attenuate increased cAMP response element-binding protein (CREB) levels that have been attributed to enhanced emotional reactivity in SZ. Enhanced dopamine D2 receptor sensitivity and signaling in the mesolimbic pathway of the brain are hallmarks of SZ. Therefore, in the present study we modeled D2 supersensitivity in Sprague-Dawley rats via neonatal injections of quinpirole (NQ) or saline (NS). NQ or NS-treated rats were bred together to produce an F1 generation of animals that exhibit phenotypes similar to that of NQ-treated parents. The F1 rats were tested on pre-pulse inhibition (PPI), a measure of sensorimotor gating, on post-natal days (P) 44-48. PPI has previously been used in clinical settings to screen antipsychotic medications. Prior to testing, rats received an injection of saline, mGlu5 positive allosteric modulator CDPPB (10 or 30 mg/kg), or A(2A) agonist CGS21680 (.03 or .09 mg/kg). On P50 brain tissue was harvested. The nucleus accumbens (NAc) was dissected from each subject and tissue was analyzed for CREB via enzyme-linked immunosorbent assay (ELISA). Results demonstrated that rats with at least one NQ-treated parent demonstrated PPI deficits that were generally alleviated by CDPPB or CGS21680, with dose-response changes across certain groups. In general, CGS21680 showed greater efficacy towards alleviation of PPI deficits. Both CDPPB and CGS21680 were successful in reducing CREB to control levels. Overall, the findings suggest that targeting mGlu5 or A(2A) receptors attenuates behavioral and proteomic abnormalities associated with psychosis.