Sex-specific long-term alteration of hippocampal excitation/inhibition balance and behavior by transient caffeine exposure during synaptogenesis
- 1ESPCI, CNRS UMR 8249, PSL University, 75005 Paris, France
Abstract
Caffeine is the most widely consumed psychoactive substance worldwide, yet the long-term consequences of exposure during critical periods of brain development remain incompletely understood. Synaptogenesis represents a vulnerable window during which environmental factors can shape the maturation of neuronal circuits and influence lifelong brain function. Here, we investigated the impact of caffeine exposure during hippocampal synaptogenesis on synaptic development, neuronal function, behavior, and seizure susceptibility, with a particular focus on sex-dependent effects. Developmental caffeine exposure induced distinct, sex-specific trajectories of hippocampal synaptic remodeling. In the CA1 region, caffeine produced opposite patterns of glutamatergic synapse regulation, characterized by a delayed reduction in excitatory synapse density in males and an increase in females. In contrast, inhibitory synapse organization was selectively altered in males, with a transient increase in CA3 inhibitory synaptic density during development associated with enhanced inhibitory transmission, whereas females exhibited no significant changes. These findings reveal sex-specific and temporally divergent effects of developmental caffeine exposure on hippocampal synaptic maturation and function. At the behavioral level, developmental caffeine exposure produced distinct sex-dependent phenotypes : males exhibited increased anxiety-like behavior, whereas females developed a delayed impairment in recognition memory that became apparent only in adulthood. Furthermore, caffeine exposure selectively increased PTZ-induced seizure susceptibility in juvenile females, an effect that was no longer detected in adulthood. Together, these findings demonstrate that caffeine exposure during hippocampal synaptogenesis induces sex-specific and temporally dynamic alterations in circuit maturation, resulting in distinct behavioral and neuronal excitability outcomes. These results highlight the importance of considering both sex and developmental timing when assessing the neurodevelopmental consequences of caffeine exposure.
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BibTeX
@misc{rimbert2026sexspecific,
title = {{Sex-specific long-term alteration of hippocampal excitation/inhibition balance and behavior by transient caffeine exposure during synaptogenesis}},
author = {S. Rimbert and J. Pressey and F. Gomez-Castro and Z. Imani and M. Russeau and D. Blum and M. NOSTEN-BERTRAND and S. Levi},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747753},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747753v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Sex-specific long-term alteration of hippocampal excitation/inhibition balance and behavior by transient caffeine exposure during synaptogenesis
AU - S. Rimbert
AU - J. Pressey
AU - F. Gomez-Castro
AU - Z. Imani
AU - M. Russeau
AU - D. Blum
AU - M. NOSTEN-BERTRAND
AU - S. Levi
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747753
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747753v1
AB - Caffeine is the most widely consumed psychoactive substance worldwide, yet the long-term consequences of exposure during critical periods of brain development remain incompletely understood. Synaptogenesis represents a vulnerable window during which environmental factors can shape the maturation of neuronal circuits and influence lifelong brain function. Here, we investigated the impact of caffeine exposure during hippocampal synaptogenesis on synaptic development, neuronal function, behavior, and seizure susceptibility, with a particular focus on sex-dependent effects. Developmental caffeine exposure induced distinct, sex-specific trajectories of hippocampal synaptic remodeling. In the CA1 region, caffeine produced opposite patterns of glutamatergic synapse regulation, characterized by a delayed reduction in excitatory synapse density in males and an increase in females. In contrast, inhibitory synapse organization was selectively altered in males, with a transient increase in CA3 inhibitory synaptic density during development associated with enhanced inhibitory transmission, whereas females exhibited no significant changes. These findings reveal sex-specific and temporally divergent effects of developmental caffeine exposure on hippocampal synaptic maturation and function. At the behavioral level, developmental caffeine exposure produced distinct sex-dependent phenotypes : males exhibited increased anxiety-like behavior, whereas females developed a delayed impairment in recognition memory that became apparent only in adulthood. Furthermore, caffeine exposure selectively increased PTZ-induced seizure susceptibility in juvenile females, an effect that was no longer detected in adulthood. Together, these findings demonstrate that caffeine exposure during hippocampal synaptogenesis induces sex-specific and temporally dynamic alterations in circuit maturation, resulting in distinct behavioral and neuronal excitability outcomes. These results highlight the importance of considering both sex and developmental timing when assessing the neurodevelopmental consequences of caffeine exposure.
ER -