Modulation of 40 Hz Gamma Synchrony in the prefrontal cortex by Clozapine and Risperidone: role for 5HT2A?
Abstract
Gamma oscillations (~ 40 Hz) are essential for perception, attention, and working memory. Disruptions in gamma synchrony are well-documented in schizophrenia and other psychiatric disorders. The 40 Hz auditory steady-state response (ASSR), an EEG measure of neural entrainment to a 40 Hz click train, is a key translational biomarker. Given its sensitivity to neurotransmitter systems and cognitive impairments, the 40 Hz ASSR is increasingly employed in neuropsychiatric drug development. Our previous work showed that clozapine, an atypical antipsychotic with broad receptor affinity (serotonergic, dopaminergic, muscarinic), robustly enhances 40 Hz ASSR via rapid phase resetting in the prefrontal cortex (PFC), outperforming haloperidol. We have now investigated risperidone, an atypical antipsychotic with selective serotonergic and dopaminergic affinity, for its effect on the 40 Hz ASSR. Sprague-Dawley rats (M&F, N=15) were implanted with epidural PFC electrodes (2.5 mm anterior, 0.8 mm lateral to bregma) and cerebellar ground/reference electrodes. After recovery, they received vehicle, clozapine (5 mg/kg), or risperidone (0.5 or 1 mg/kg) in a crossover design, with doses mimicking clinical exposure. EEG (Signal 7.0; CED1401 Micro 3) was recorded during 40 Hz click trains (~1 ms, ~65 dB SPL) over house speakers. Each 3 s EEG sweep included a 1 s click train, with 75 trials/rat. Sixty minutes post-treatment, EEG entrainment at 40 Hz was observed in the PFC across all groups. Relative to vehicle, risperidone dose-dependently enhanced gamma synchrony (0.5 mg/kg < 1 mg/kg), with the higher dose producing effects comparable to clozapine (5 mg/kg). Significant cataleptic effects were observed with risperidone (1 mg/kg) but not clozapine. Since haloperidol (high D2 affinity) does not enhance gamma synchrony and risperidone lacks significant muscarinic (M1/M4) activity, we speculate that serotonergic (e.g.,5HT2A) activity underlies these effects. Future studies will investigate receptor mechanisms to understand how atypical antipsychotics enhance gamma synchrony and cognition in psychiatric disorders.
Start Time
16-4-2025 1:30 PM
End Time
16-4-2025 2:30 PM
Room Number
304
Presentation Type
Oral Presentation
Presentation Subtype
Grad/Comp Orals
Presentation Category
Science, Technology and Engineering
Faculty Mentor
Siva Digavalli
Modulation of 40 Hz Gamma Synchrony in the prefrontal cortex by Clozapine and Risperidone: role for 5HT2A?
304
Gamma oscillations (~ 40 Hz) are essential for perception, attention, and working memory. Disruptions in gamma synchrony are well-documented in schizophrenia and other psychiatric disorders. The 40 Hz auditory steady-state response (ASSR), an EEG measure of neural entrainment to a 40 Hz click train, is a key translational biomarker. Given its sensitivity to neurotransmitter systems and cognitive impairments, the 40 Hz ASSR is increasingly employed in neuropsychiatric drug development. Our previous work showed that clozapine, an atypical antipsychotic with broad receptor affinity (serotonergic, dopaminergic, muscarinic), robustly enhances 40 Hz ASSR via rapid phase resetting in the prefrontal cortex (PFC), outperforming haloperidol. We have now investigated risperidone, an atypical antipsychotic with selective serotonergic and dopaminergic affinity, for its effect on the 40 Hz ASSR. Sprague-Dawley rats (M&F, N=15) were implanted with epidural PFC electrodes (2.5 mm anterior, 0.8 mm lateral to bregma) and cerebellar ground/reference electrodes. After recovery, they received vehicle, clozapine (5 mg/kg), or risperidone (0.5 or 1 mg/kg) in a crossover design, with doses mimicking clinical exposure. EEG (Signal 7.0; CED1401 Micro 3) was recorded during 40 Hz click trains (~1 ms, ~65 dB SPL) over house speakers. Each 3 s EEG sweep included a 1 s click train, with 75 trials/rat. Sixty minutes post-treatment, EEG entrainment at 40 Hz was observed in the PFC across all groups. Relative to vehicle, risperidone dose-dependently enhanced gamma synchrony (0.5 mg/kg < 1 mg/kg), with the higher dose producing effects comparable to clozapine (5 mg/kg). Significant cataleptic effects were observed with risperidone (1 mg/kg) but not clozapine. Since haloperidol (high D2 affinity) does not enhance gamma synchrony and risperidone lacks significant muscarinic (M1/M4) activity, we speculate that serotonergic (e.g.,5HT2A) activity underlies these effects. Future studies will investigate receptor mechanisms to understand how atypical antipsychotics enhance gamma synchrony and cognition in psychiatric disorders.