CNS*2026 Halifax

Introduction
Auditory processing deficits are a core feature of schizophrenia (SZ). The N1 component of the auditory evoked potential (AEP) is reduced in SZ. N1 refractory curves describe increasing N1 amplitudes with longer inter-stimulus intervals (ISIs), suggesting dependence on slow synaptic mechanisms, including GABAB and NMDA receptors. Using a biophysical model of macaque primary auditory cortex (A1) and thalamus [1], we examine how GABAB and NMDA modulation shape N1 dynamics. We further test whether GABAB modulation can counteract N1 amplitude reductions under NMDA hypofunction. Our goal is to reproduce in-vivo N1 deficits and identify circuit mechanisms relevant to SZ.


Methods
Simulations were performed using the NEURON simulation environment and NetPyNE multiscale modeling package [2,3]. The model includes medial geniculate nucleus (MGN), thalamic reticular nucleus (TRN), and primary auditory cortex (A1). A1 is represented as a cortical column with over 12,000 neurons and ~25 million synapses. The model captures multiscale activity, including laminar local field potentials (LFPs), current source density (CSD; second spatial derivative of LFP), and neuronal firing rates. Auditory stimuli are modeled as punctate thalamic inputs to core and matrix pathways. Simulated LFPs are used to derive CSD, and resulting patterns are compared with in-vivo macaque data for validation.


Results
Brief thalamic stimulation evoked CSD sink events in A1 granular layers that closely matched in-vivo macaque responses. The model reproduced the N1 refractory curve, with event-related CSD amplitude and multi-unit activity increasing with longer inter-stimulus intervals (ISI). This relationship was strongly governed by GABAB conductance: increasing GABAB (+25%) reduced N1 amplitude across layers, most prominently in supragranular and infragranular groups, while decreasing GABAB (-25%) enhanced N1 responses. In contrast, NMDA conductance modulation (+/-25%) produced comparatively modest effects, suggesting weaker sensitivity under current conditions.


Discussion
We investigated N1 refractory dynamics by examining inter-stimulus interval dependence of GABAB conductance in the A1 model. Increased GABAB reduced N1 amplitude across layers, suggesting a potential contributory role in auditory processing deficits observed in SZ. NMDA conductance modulation produced comparatively modest effects on N1 under current conditions. Notably, reducing GABAB-enhanced N1 responses, indicating a potential compensatory mechanism for N1 reductions associated with NMDA channel hypofunction. The model reproduces key in-vivo N1 dynamics and provides a framework for probing circuit mechanisms. Future work will extend this approach to more complex responses, including mismatch negativity, which is disrupted in SZ.


References

1. Dura-Bernal, S., et al. (2023). Data-driven multiscale model of macaque auditory thalamocortical circuits. Cell Reports, 42(11), 113378.

2. Dura-Bernal, S., et al. (2019). NetPyNE, a tool for data-driven multiscale modeling of brain circuits. eLife, 8, e44494.

3. Hines, M. L., & Carnevale, N. T. (2001). NEURON: A tool for neuroscientists. Neuroscientist, 7(2), 123–135.

Acknowledgement
Research supported by NIH R01DC019979,  NIH R01DC012947,  NIH R01NS128924-01, NIH R01MH134118-01, NIH P50MH109429, ARL Cooperative Agreement W911NF2220143