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bioRxiv · 10.1101/2025.08.30.673226

Aberrant development of glutamatergic inputs to PV and SOM interneurons shape amygdala excitability and oscillatory dynamics after early life stress

Shteinikov, V.·Rhee, J.·Ojanen, S.·Kunnari, A.-J.·Haikonen, J.·Picard, M.·Litkey, O.·Lakstygal, A.·Hartung, H.·Lauri, S.
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Abstract

Early-life stress (ELS) induces persistent amygdala dysfunction and affects amygdala-related emotional behaviors, yet the developmental and physiological mechanisms driving these effects remain poorly understood. Here, we provide a comprehensive electrophysiological characterization of the effects of ELS on parvalbumin and somatostatin interneurons (INs) as well as principal neurons (PNs) in the mouse lateral amygdala (LA) across development. Additionally, we correlate these findings to activity of the LA circuitry in vivo, using Neuropixels recordings in awake mice. In preweaning juveniles, the effects of ELS were remarkably similar in males and females, involving reduced IN excitability, elevated glutamatergic input to INs and shift in the PN E/I balance. While IN function was largely normalized in adult females, males developed a distinct pathological phenotype characterized by reduced glutamatergic input to INs, impaired recruitment of INs and hyperexcitability of PNs. This male-specific dysfunction correlated with aberrant LA oscillatory dynamics in awake mice and deficits in fear processing. Our data suggest that the impaired glutamatergic wiring of interneurons is a key mechanism underlying the aberrant circuit dynamics in the LA after ELS exposure and contribute to the ELS-induced defects in fear processing. These findings highlight sex-specific developmental trajectories of interneuron connectivity as a potential factor contributing to ELS-induced psychiatric vulnerability.

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Shteinikov, V., Rhee, J., Ojanen, S., Kunnari, A.-J., Haikonen, J., Picard, M., Litkey, O., Lakstygal, A., Hartung, H., Lauri, S.. 2025-08-31. Aberrant development of glutamatergic inputs to PV and SOM interneurons shape amygdala excitability and oscillatory dynamics after early life stress. https://doi.org/10.1101/2025.08.30.673226

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