• Kimbra A Edwards and Susan L Zup.
• Graduate Program in Developmental and Brain Sciences, University of Massachusetts Boston, Boston, MA 02125, USA; Psychology Department, University of Massachusetts Boston, Boston, MA 02125, USA.
• Neuroscience. 2021 May 21; 463: 184-196.

AbstractNeuronal excitability and susceptibility to excitotoxic damage can be sex-specific, with neurons from males usually being more 'easily excitable' compared to neurons from females, especially during development. Increased excitability at an individual neuronal level can lead to the formation of hyperexcitable neuronal networks, which, consequently can make the brain more seizure prone. Both animal and clinical data suggest that males experience more frequent and severe seizures than do females. Serotonin (5-hydroxytryptamine; 5-HT) can mediate neuronal excitability and seizure behavior, often serving as an anticonvulsant. Importantly, 5-HT signaling during parts of the perinatal period is sexually dimorphic. Sex differences during development have been reported in both serotonin levels and receptor type (excitatory vs. inhibitory) expression in a manner that may leave the male brain more vulnerable to over-excitation. Thus, we aimed to determine if the anticonvulsant effects of 5-HT were sex- and/or age-dependent in juvenile animals. We report a baseline sex difference in N-methyl-d-aspartate (NMDA)-induced seizure behavior and hippocampal neuronal loss, with postnatal day (PND) 14 males exhibiting more severe seizure behavior compared to females. Pretreatment with the general 5-HT receptor agonist 5-methoxytryptamine (5-MT) abolishes baseline sex differences, providing an anticonvulsant effect for males only. These sex differences appear to be at least in part organized by testosterone, as females given neonatal androgen exhibit a seizure behavior profile in between that of males and females.Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

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