Latent sex differences in mechanisms of estradiol-induced excitatory synaptic potentiation in the hippocampus


One of the most fascinating observations in the brain is that the neural connections change with experience and this phenomenon is called synaptic plasticity. Patterns of activity or neuromodulators can acutely induce changes in the synaptic strength in the brain. My thesis is focused on understanding the mechanisms of plasticity at the CA3-CA1 synapses in the hippocampus. Specifically, we studied the role of 17β-estradiol (E2) as a neuromodulator. Although, E2 is classically studied as a sex hormone, recent evidence shows that E2 can be locally synthesized in the hippocampus. Moreover, E2 can acutely potentiate excitatory synaptic transmission in the hippocampus. However, the mechanisms that underlie E2-induced potentiation are not well understood. More fundamentally in the hippocampus, the mechanisms of synaptic plasticity have been compared between males and females only in limited studies. In our experiments, we compared the acute E2 effect on excitatory synaptic transmission in both sexes. Through different electrophysiological experiments we found that E2 can acutely potentiate excitatory synaptic transmission very similarly in both sexes. Furthermore, this potentiation is synapse specific and occurs largely by independent pre or postsynaptic mechanisms in both sexes. While investigating molecular signaling that underlies E2-potentiation in both sexes, we found that although the overall magnitude of E2-potentiation is similar between sexes, the underlying molecular mechanisms differ. First, we observed a sex difference in the requirement of different estrogen receptors (ERs). We found that different ERs not only participate in pre or postsynaptic components of potentiation, but their requirements are different between sexes. Downstream of ERs, we found that the requirement of kinases like PKA and calcium sources like internal stores and L-type calcium channels also differ between sexes. Conversely, the requirement of some kinases like Src, ROCK, MAPK and CAMKII was similar between sexes. Investigating downstream postsynaptic mechanisms revealed that either an increase in AMPAR number or conductance could underlie E2-potentiation. In females, majority of E2-responsive spines show an increase in conductance, while in males half of the E2-responsive spines show an increase in conductance and the other half show an increase in number. Moreover, we found that in females this increase in conductance occurs due to replacement with calcium permeable AMPARs at the synapses following E2-application. Interestingly, we found that the sex difference in the requirement of PKA is generalizable to long term potentiation, which is one of the most commonly studied synaptic plasticity phenomenon at these synapses. Overall, our studies have described the role of different molecular signaling components that underlie E2-induced excitatory synaptic potentiation. We found that E2-potentiation can occur via activation of multiple signaling cascades and moreover, some of these signaling pathways are different between sexes. Sex differences in the mechanisms of synaptic plasticity in a non-reproductive brain region like the hippocampus fills a gap in our understanding of synaptic plasticity. Moreover, it aids future research to broaden the therapeutic strategies with the possibility of sex-specific therapeutics to treat neurological and neuropsychiatric disorders.

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