Sex-specific dynamics of activity-dependent regulation of synaptic CaMKII
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.
Significance Statement: Neuronal sex differences are commonly studied in reproductive circuits or when neuronal structure or function differs overtly between males and females. However, similar physiological and behavioral outcomes may hide distinct underlying molecular mechanisms. Here, we show that both steady-state CaMKII protein levels and activity-dependent changes in CaMKII differ between female and male flies at the larval neuromuscular junction and in adult mushroom body neurons. These differences are downstream of the sex-determination pathway but occur without overt changes in behavioral output. Our findings reveal a hidden layer of sexual dimorphism in the dynamic regulation of synaptic proteins, demonstrating that equivalent function need not reflect equivalent molecular mechanisms. Such differences may contribute to sex-specific vulnerabilities to neurological and psychiatric disorders.
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BibTeX
@misc{sharma2026sexspecific,
title = {{Sex-specific dynamics of activity-dependent regulation of synaptic CaMKII}},
author = {Ankit Sharma and Kelsey J. Clements and Natalie D’Ambra and Julia Birnbaum and Elena A. Kuklin and Martha L. Reed and Leslie C. Griffith},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.760771},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760771v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Sex-specific dynamics of activity-dependent regulation of synaptic CaMKII
AU - Ankit Sharma
AU - Kelsey J. Clements
AU - Natalie D’Ambra
AU - Julia Birnbaum
AU - Elena A. Kuklin
AU - Martha L. Reed
AU - Leslie C. Griffith
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.760771
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.760771v1
AB - 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. Significance Statement: Neuronal sex differences are commonly studied in reproductive circuits or when neuronal structure or function differs overtly between males and females. However, similar physiological and behavioral outcomes may hide distinct underlying molecular mechanisms. Here, we show that both steady-state CaMKII protein levels and activity-dependent changes in CaMKII differ between female and male flies at the larval neuromuscular junction and in adult mushroom body neurons. These differences are downstream of the sex-determination pathway but occur without overt changes in behavioral output. Our findings reveal a hidden layer of sexual dimorphism in the dynamic regulation of synaptic proteins, demonstrating that equivalent function need not reflect equivalent molecular mechanisms. Such differences may contribute to sex-specific vulnerabilities to neurological and psychiatric disorders.
SN - 2692-8205
ER -