Pharmacological evidence for GluN2A receptor mediation of click train induced 40 Hz neural synchrony in rodent prefrontal and temporal cortices
Abstract
Gamma oscillations (30-100 Hz), generated by interactions between parvalbumin (PV)-positive interneurons and pyramidal cells, are a signature of sensory processing in the neocortex. A reliable method to engage these networks across species is through rhythmic auditory stimulation at gamma frequency (~ 40 Hz), which robustly entrains local field potentials with high precision and modulates gain. Converging evidence indicates that NMDA receptor activity on PV interneurons is required for 40 Hz synchrony: genetic ablation of NMDA receptors on PV interneurons in mice and acute NMDA blockade in rodents and humans, robustly disrupt this response, while response to lower frequency (~ 20 Hz) stimulus is unaffected. Moreover, in schizophrenia patients where reduced NMDA function has been implicated, consistent entrainment deficits are noted at 40 Hz but not at 20 Hz. NMDA receptors are heterotetramers composed of two obligatory GluN1 subunits and two GluN2 subunits (A-D), but the specific GluN2 subtype critical for 40 Hz gamma synchrony remains unknown. Recent genetic studies link rare and common variants in the gene encoding GluN2A subunit to substantial schizophrenia risk, highlighting a compelling target for drug development. In this study, we investigated the role of GluN2A in gamma synchrony using male and female Sprague-Dawley rats implanted with epidural EEG electrodes over prefrontal and temporal cortices. EEG was recorded (Signal 8.02; CED1401 Micro 3) during click train presentations (1 ms sq waves at 40 or 20 Hz, ~65 dB SPL) played over house speakers. Each 5 s EEG sweep included a 1-2 s click train, with 75 trials/rat. In a balanced crossover design, rats received either saline (1 ml/kg) or the GluN2A-preferring competitive antagonist PEAQX (60 mg/kg, s.c.). Sixty minutes post-treatment, intertrial phase coherence (ITPC), a marker of trial-to-trial response consistency, was evaluated in temporal segments corresponding to prestimulus, during and post-stimulus periods. In the during stimulus period only, PEAQX significantly reduced ITPC in response to 40 Hz stimulation at both frontal and temporal sites (p < 0.05), while ITPC to 20 Hz click trains was unaffected (p > 0.05). These findings provide the first direct evidence that GluN2A subunits mediate 40 Hz auditory steady-state responses in vivo. Combined with clinical data showing reduced 40 Hz synchrony in schizophrenia, our results suggest that impaired GluN2A function may underlie circuit-level deficits in the disorder and support the therapeutic potential of targeting GluN2A augmentation as a promising strategy for new drug development.
Start Time
15-4-2026 9:00 AM
End Time
15-4-2026 12:00 PM
Room Number
Culp Ballroom 316
Poster Number
49
Presentation Type
Poster
Presentation Subtype
Posters - Competitive
Presentation Category
Health
Student Type
Graduate and Professional Degree Students, Residents, Fellows
Faculty Mentor
Sivarao Digavalli
Pharmacological evidence for GluN2A receptor mediation of click train induced 40 Hz neural synchrony in rodent prefrontal and temporal cortices
Culp Ballroom 316
Gamma oscillations (30-100 Hz), generated by interactions between parvalbumin (PV)-positive interneurons and pyramidal cells, are a signature of sensory processing in the neocortex. A reliable method to engage these networks across species is through rhythmic auditory stimulation at gamma frequency (~ 40 Hz), which robustly entrains local field potentials with high precision and modulates gain. Converging evidence indicates that NMDA receptor activity on PV interneurons is required for 40 Hz synchrony: genetic ablation of NMDA receptors on PV interneurons in mice and acute NMDA blockade in rodents and humans, robustly disrupt this response, while response to lower frequency (~ 20 Hz) stimulus is unaffected. Moreover, in schizophrenia patients where reduced NMDA function has been implicated, consistent entrainment deficits are noted at 40 Hz but not at 20 Hz. NMDA receptors are heterotetramers composed of two obligatory GluN1 subunits and two GluN2 subunits (A-D), but the specific GluN2 subtype critical for 40 Hz gamma synchrony remains unknown. Recent genetic studies link rare and common variants in the gene encoding GluN2A subunit to substantial schizophrenia risk, highlighting a compelling target for drug development. In this study, we investigated the role of GluN2A in gamma synchrony using male and female Sprague-Dawley rats implanted with epidural EEG electrodes over prefrontal and temporal cortices. EEG was recorded (Signal 8.02; CED1401 Micro 3) during click train presentations (1 ms sq waves at 40 or 20 Hz, ~65 dB SPL) played over house speakers. Each 5 s EEG sweep included a 1-2 s click train, with 75 trials/rat. In a balanced crossover design, rats received either saline (1 ml/kg) or the GluN2A-preferring competitive antagonist PEAQX (60 mg/kg, s.c.). Sixty minutes post-treatment, intertrial phase coherence (ITPC), a marker of trial-to-trial response consistency, was evaluated in temporal segments corresponding to prestimulus, during and post-stimulus periods. In the during stimulus period only, PEAQX significantly reduced ITPC in response to 40 Hz stimulation at both frontal and temporal sites (p < 0.05), while ITPC to 20 Hz click trains was unaffected (p > 0.05). These findings provide the first direct evidence that GluN2A subunits mediate 40 Hz auditory steady-state responses in vivo. Combined with clinical data showing reduced 40 Hz synchrony in schizophrenia, our results suggest that impaired GluN2A function may underlie circuit-level deficits in the disorder and support the therapeutic potential of targeting GluN2A augmentation as a promising strategy for new drug development.
