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bioRxiv · 10.1101/2025.11.22.689933

Sensory Circuit Dynamics in a Mouse Model of Epileptic Encephalopathy

Suchanek, D.·Williams, A.·Cao, T.·Todd, W. D.·Sun, Q.-Q.
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Abstract

Epileptic encephalopathies (EEs) are severe developmental disorders with abnormal EEG activity that worsens neurodevelopmental deficits, yet underlying sensory and cognitive impairment mechanisms are unclear. We studied cortical circuit dynamics in Ank3-1b-/- mice, an EE model with parvalbumin interneuron dysfunction, using laminar electrophysiology, spike-field coherence (SFC), single-unit analyses, and behavioral assays. Ank3-1b-/- mice showed disrupted excitatory-inhibitory (E-I) balance, with reduced sink/source ratios (p = 0.0279) and elevated net currents (AVREC; p < 0.01), indicating hyperexcitability. In awake states, sensory-evoked intra-columnar connectivity was impaired, with lower Pearson correlations (p < 0.001) and increased low-frequency (3-30 Hz) SFC (p < 0.001), but intact gamma-band coherence, suggesting aberrant synchronization. Inhibitory neuron latencies were delayed in infragranular layers under anesthesia (p < 0.001) and supragranular layers when awake (p = 0.005), implying thalamocortical deficits. Despite preserved sensory adaptation and recognition memory, Ank3-1b-/- mice exhibited heightened anxiety (p < 0.05) and variable circadian rhythms, indicating selective affective and regulatory deficits. These results show that Ank3-1b loss disrupts cortical E-I balance and synchrony, delaying sensory processing, while compensatory mechanisms maintain critical sensory functions. This study links ANK3 mutations to layer-specific circuit dysfunction, offering insights into EE pathophysiology and sensory deficits.

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Suchanek, D., Williams, A., Cao, T., Todd, W. D., Sun, Q.-Q.. 2025-11-25. Sensory Circuit Dynamics in a Mouse Model of Epileptic Encephalopathy. https://doi.org/10.1101/2025.11.22.689933

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