Caffeine intake during lactation has a sex-dependent effect on the hippocampal excitatory/inhibitory balance and pups' behavior.

During early life, disruptions in glutamatergic and GABAergic synapse development in the hippocampus may contribute to several neurodevelopmental disorders, including cognitive deficits and psychiatric disorders. Caffeine is the most consumed psychoactive drug in the world, and previous work from our group has shown that caffeine disrupts visual system connections at different stages of development. This work aimed to investigate the effects of caffeine consumption during lactation in the glutamatergic and GABAergic synaptic markers in the hippocampus and on the behavior of rat offspring. We found that maternal caffeine intake significantly reduced GluN1 subunits of the NMDA receptor, increased the GluA1/GluA2 ratio of AMPA receptor in the dorsal hippocampus, and decreased GAD content in female pups' ventral hippocampus. On the other hand, an increase in GluN1/GluN2b subunits, a decrease in GAD content in the dorsal hippocampus, and a reduction of the GluA1 content in the ventral hippocampus were observed in male pups. In addition, changes in the behavior of the offspring submitted to indirect caffeine consumption were also sex-dependent, with females developing anxiety-like behavior and males showing anxiety-like behavior and hyper-locomotion. These results highlight that maternal caffeine intake promotes changes in the hippocampal excitatory and inhibitory balance and offspring behavior in a sex-dependent manner, suggesting that the population should be alerted to reduced caffeine consumption by breastfeeding mothers.