Sex-specific maturational trajectory of endocannabinoid plasticity in the rat prefrontal cortex

Abstract

The prefrontal cortex (PFC) develops until early adulthood in rodents and humans, but how synaptic plasticity evolves throughout postnatal development is not known. Here, we used a cross-sectional approach to establish the postnatal maturational trajectories of intrinsic properties and synaptic plasticity in the PFC of rats of both sexes. We found that while layer 5 PFC pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases and resting potentials across all age groups, excitability was lower in female adults compared to the other developmental stages. NMDAR-dependent long-term potentiation and mGluR2/3-mediated long-term depression (LTD) were equally expressed at the juvenile, pubescent and adult developmental stages in animals of both sexes. However, the developmental course of endocannabinoid (eCB)-mediated LTD was sexually dimorphic. First, eCB-LTD started at the juvenile period in females, but although CB1R were functional in both sexes at all developmental stages, eCB-LTD’s first manifestation was delayed to pubescence in male. Second, eCB-LTD engaged distinct receptors in male and female depending on their developmental stages. Female rats employ both CB1R and TRPV1R to produce eCB-LTD at the juvenile stage but solely CB1R at pubescence followed by only TRPV1R at adulthood. In contrast, in pubescent and adult males eCB-LTD always and exclusively depended on CB1R. Pharmacological blockade of 2AG’s principal degrading enzyme allowed incompetent male juvenile synapses to express eCB-LTD. The data reveal different maturational trajectories in the PFC of male and female rats and provide new cellular substrates to the sex-specific behavioral and synaptic abnormalities caused by adolescent exposure to cannabinoids.

Sex differences in the medial prefrontal cortical glutamate system

“…In line with this hypothesis, the number of action potentials in response to depolarizing steps is lower in adult females than pubescent or juvenile females, an effect of age that is not seen in males [ 53 ]. This recapitulates previously published data demonstrating prepubescent females have enhanced excitability in medium spiny neurons within the striatum compared to males [ 54 ].…”

“…Nonetheless, there are reported aspects of transmission in this region that do not differ between males and females. Maturational trajectories of current–voltage curves, resting membrane potentials, rheobases, mGluR2/3-mediated LTD, and paired pulse ratios in layer V of the PFC are similar between the sexes in rats [ 53 ]. Additionally, field excitatory postsynaptic potentials are similar between the sexes across multiple age groups [ 53 ].…”

“…Maturational trajectories of current–voltage curves, resting membrane potentials, rheobases, mGluR2/3-mediated LTD, and paired pulse ratios in layer V of the PFC are similar between the sexes in rats [ 53 ]. Additionally, field excitatory postsynaptic potentials are similar between the sexes across multiple age groups [ 53 ]. Together, these data indicate that males and females mature similarly in many aspects of synaptic plasticity within the PFC.…”

Sex-specific divergent maturational trajectories in the postnatal rat basolateral amygdala

“…We recently showed that the input profile and the release probability of excitatory synapses to prefrontal cortex (PFC) pyramidal neurons were consistent between pubescence and adulthood in both sexes ( Bernabeu et al., 2020 ). In the BLA, the input-output curves built in pubescent rats reached higher maxima than in adults, in support of the idea that the BLA reaches maturity late in life.…”

Early Consumption of Cannabinoids: From Adult Neurogenesis to Behavior

“…The ECS plays a specific role in neural development by controlling the establishment of cortical-subcortical connections [ 46 ]. In this regard, a study by Bernabeu et al (2020) analyzed the postnatal maturation trajectories of layer 5 pyramidal PFC synapses at different postnatal stages [ 53 ]. They found that endocannabinoid-mediated long-term depression (LTD) was sexually dimorphic, even though CB1s were functional in both sexes during all developmental stages.…”