The Sexual Dimorphic Synapse: From Spine Density to Molecular Composition

Abstract

A synaptic sexual dimorphism is relevant in the context of multiple neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. Many of these disorders show a different prevalence and progression in woman and man. A similar variance is also present in corresponding animal models. To understand and characterize this dimorphism in pathologies it is important to first understand sex differences in unaffected individuals. Therefore, sexual differences have been studied since 1788, first focusing on brain weight, size, and volume. But as these measures are not directly related to brain function, the investigation of sexual dimorphism also expanded to other organizational levels of the brain. This review is focused on sexual dimorphism at the synaptic level, as these specialized structures are the smallest functional units of the brain, determining cell communication, connectivity, and plasticity. Multiple differences between males and females can be found on the levels of spine density, synaptic morphology, and molecular synapse composition. These differences support the importance of sex-disaggregated data. The specificity of changes to a particular brain region or circuit might support the idea of a mosaic brain, in which each tile individually lies on a continuum from masculinization to feminization. Moreover, synapses can be seen as the smallest tiles of the mosaic determining the classification of larger areas.

Age and sex effects on paired-pulse suppression and prepulse inhibition of auditory evoked potentials

“…Sex differences have been reported in the brain that are independent of gonadal hormone levels ( Ingalhalikar et al, 2014 ; Pandya et al, 2019 ; Gegenhuber and Tollkuhn, 2020 ; Williams et al, 2021 ). Among them, differences in inhibitory synaptic transmission appear to be important ( Uhl et al, 2022 ). The excitability of a neural circuit is controlled by excitatory pyramidal neurons and inhibitory interneurons.…”

The effects of GPER on age-associated memory impairment induced by decreased estrogen levels

“…Memory impairment induced by normal age or age-related diseases is the primary neurodegenerative symptom leading to biochemical changes in some brain regions, an imperative structure among which is the hippocampus ( Wang et al, 2020 ). And the hippocampus is a brain region that is extremely sensitive to E2 ( Uhl et al, 2022 ). Immunohistochemical studies in the rodent brain show that GPER is colocalized with pyramidal cells in every region of the hippocampus (CA1-3) and granule cells in the dentate gyrus (DG) and is especially dense in the stratum lucidum of CA3 ( Waters et al, 2015 ; Mahmoud et al, 2016 ).…”

Sex differences in gene regulatory networks during mid-gestational brain development

“…Neurotransmitters are essential for cell migration due to its chemotropic effects on migrating neurons (Behar et al, 1996), and there is abundant evidence that neurotransmitters and their receptors modulate gene expression through calcium and CREB signaling pathways impacting on neurogenesis, neuronal differentiation and programmed cell death (Jagasia et al, 2009;Ascenzi and Bony, 2017). Studies with animal models have demonstrated neurochemical differences between males and females, mostly due to sex hormones action (Uhl et al, 2022), and our results corroborate the hypothesis that during corticogenesis estrogen is a relevant signaling molecule (Denley et al, 2018). In a similar fashion, cytokines are critical signaling factors for the renewal of neural stem cells, regulation of differentiation between neurons and glial cells, determination of neuronal identity, and chemotropism, modifying cell migration and axon guidance (Deverman and Patterson, 2009).…”