Acceleration of 40 Hz gamma oscillatory phase resetting in the prefrontal cortex by clozapine and risperidone: role for 5HT2A?
Abstract
Gamma oscillations (~ 40Hz) are essential for sensory perception, attention, and working memory. Disruptions in gamma synchrony are well-documented in schizophrenia and other psychiatric disorders. The 40Hz auditory steady-state response (ASSR) is an EEG measure of cortical entrainment to 40Hz click-trains. Given its sensitivity to key neurotransmitter systems as well as a modest correlation with cognitive function, the 40Hz ASSR is increasingly employed as a biomarker in neuropsychiatric drug development for bench-to-bedside translation. Our previous work showed clozapine, an atypical antipsychotic with broad receptor affinities (serotonergic, dopaminergic, muscarinic), but not haloperidol, a high-affinity D2 antagonist, robustly accelerated gamma oscillations through phase resetting in the prefrontal cortex (PFC). We have now investigated risperidone, another atypical antipsychotic with selective serotonergic and dopaminergic affinity, for its effect on the 40Hz ASSR. SpragueDawley rats (M&F, N=15) were implanted with an epidural prefrontal electrode and referred to cerebellar electrodes. Post-recovery, they received vehicle, clozapine (5 mg/kg), or risperidone (0.5 or 1 mg/kg) in crossover designs anchored to clinically relevant drug exposure. EEG (Signal 8.02; CED1401 Micro 3) was recorded during 40Hz click trains (~1 ms, ~65 dB SPL) played over house speakers. Each 3s EEG sweep included a 1s click train, with 75 trials/rat. Sixty minutes post-treatment, EEG entrainment at 40Hz was observed in the PFC across all groups. Relative to vehicle, risperidone dose-dependently accelerated and enhanced gamma synchrony, with higher doses producing effects comparable to clozapine. The robust increases in phase synchrony happened often with little change in evoked power, implicating gamma phase resetting. Since haloperidol (high D2 affinity) does not enhance gamma synchrony and risperidone lacks significant muscarinic (M1/M4) activity, we speculate serotonergic (5HT2A) inverse agonism could be mediating these effects. Future studies will further explore receptor mechanisms, improving our understanding of atypical antipsychotics enhancing the gamma synchrony and cognitive performance in psychiatric disorders.
Start Time
15-4-2026 9:00 AM
End Time
15-4-2026 12:00 PM
Room Number
Culp Ballroom 316
Poster Number
18
Presentation Type
Poster
Presentation Subtype
Posters - Competitive
Presentation Category
Science, Technology, and Engineering
Student Type
Graduate and Professional Degree Students, Residents, Fellows
Faculty Mentor
Sivarao Digavalli
Acceleration of 40 Hz gamma oscillatory phase resetting in the prefrontal cortex by clozapine and risperidone: role for 5HT2A?
Culp Ballroom 316
Gamma oscillations (~ 40Hz) are essential for sensory perception, attention, and working memory. Disruptions in gamma synchrony are well-documented in schizophrenia and other psychiatric disorders. The 40Hz auditory steady-state response (ASSR) is an EEG measure of cortical entrainment to 40Hz click-trains. Given its sensitivity to key neurotransmitter systems as well as a modest correlation with cognitive function, the 40Hz ASSR is increasingly employed as a biomarker in neuropsychiatric drug development for bench-to-bedside translation. Our previous work showed clozapine, an atypical antipsychotic with broad receptor affinities (serotonergic, dopaminergic, muscarinic), but not haloperidol, a high-affinity D2 antagonist, robustly accelerated gamma oscillations through phase resetting in the prefrontal cortex (PFC). We have now investigated risperidone, another atypical antipsychotic with selective serotonergic and dopaminergic affinity, for its effect on the 40Hz ASSR. SpragueDawley rats (M&F, N=15) were implanted with an epidural prefrontal electrode and referred to cerebellar electrodes. Post-recovery, they received vehicle, clozapine (5 mg/kg), or risperidone (0.5 or 1 mg/kg) in crossover designs anchored to clinically relevant drug exposure. EEG (Signal 8.02; CED1401 Micro 3) was recorded during 40Hz click trains (~1 ms, ~65 dB SPL) played over house speakers. Each 3s EEG sweep included a 1s click train, with 75 trials/rat. Sixty minutes post-treatment, EEG entrainment at 40Hz was observed in the PFC across all groups. Relative to vehicle, risperidone dose-dependently accelerated and enhanced gamma synchrony, with higher doses producing effects comparable to clozapine. The robust increases in phase synchrony happened often with little change in evoked power, implicating gamma phase resetting. Since haloperidol (high D2 affinity) does not enhance gamma synchrony and risperidone lacks significant muscarinic (M1/M4) activity, we speculate serotonergic (5HT2A) inverse agonism could be mediating these effects. Future studies will further explore receptor mechanisms, improving our understanding of atypical antipsychotics enhancing the gamma synchrony and cognitive performance in psychiatric disorders.
