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bioRxiv · 10.64898/2026.10.21.760771

Sex-specific dynamics of activity-dependent regulation of synaptic CaMKII

Sharma, A.·Clements, K. J.·D'Ambra, N.·Birnbaum, J.·Kuklin, E.·Reed, M.·Griffith, L.
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Abstract

Similar behavioral outcomes in males and females can mask substantial differences in the mechanisms underlying neuronal function. However, to what extent sex influences the abundance and activity-dependent changes of proteins that govern neuronal plasticity remains poorly understood. Here we investigated sex-specific regulation of calcium/calmodulin-dependent protein kinase II (CaMKII), an evolutionarily conserved regulator of synaptic stability and plasticity in fruit fly Drosophila melanogaster. We find that the steady state levels and activity-driven changes in CaMKII protein differ between female and male at both third instar larval neuromuscular junction (NMJ) and in adult fly mushroom body (MB). These sex-specific differences are downstream of the sex determination pathway, implicating somatic sex identity in the regulation of CaMKII abundance and its activity-dependent dynamics. Despite the differences in CaMKII levels between female and male flies, we observed no impairment of plasticity in either sex. Overall, our findings reveal sex-dependent regulation of both steady-state and activity-dependent levels of a highly conserved neuronal plasticity-associated protein across distinct neuronal contexts and development stages. These results further support the idea that females and males can achieve similar behavioral outcomes through different molecular mechanisms. Growing evidence that sexually dimorphic molecular responses contribute directly to sex differences in vulnerability to stress and disease underscores the importance of identifying these mechanisms and understanding their consequences.

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Sharma, A., Clements, K. J., D'Ambra, N., Birnbaum, J., Kuklin, E., Reed, M., Griffith, L.. 2026-10-24. Sex-specific dynamics of activity-dependent regulation of synaptic CaMKII. https://doi.org/10.64898/2026.10.21.760771

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