This review focuses on the effects of estrogens upon the cerebellum, a brain region long ignored as a site of estrogen action. Highlighted are the diverse effects of estradiol within the cerebellum, emphasizing the importance of estradiol signaling in cerebellar development, modulation of synaptic neurotransmission in the adult, and the potential influence of estrogens on various health and disease states. We also provide new data, consistent with previous studies, in which locally synthesized estradiol modulates cerebellar glutamatergic neurotransmission, providing one underlying mechanism by which the actions of estradiol can affect this brain region.

In addition to activating nuclear estrogen receptor signaling, 17β-estradiol can also regulate neuronal function via surface membrane receptors. In various brain regions, these actions are mediated by the direct association of estrogen receptors (ERs) activating metabotropic glutamate receptors (mGluRs). These ER/mGluR signaling partners are organized into discrete functional microdomains via caveolin proteins. A central question that remains concerns the underlying mechanism by which these subpopulations of ERs are targeted to the surface membrane. One candidate mechanism is S-palmitoylation, a posttranscriptional modification that affects the subcellular distribution and function of the modified protein, including promoting localization to membranes. Here we test for the role of palmitoylation and the necessity of specific palmitoylacyltransferase proteins in neuronal membrane ER action. In hippocampal neurons, pharmacological inhibition of palmitoylation eliminated 17β-estradiol-mediated phosphorylation of cAMP response element-binding protein, a process dependent on surface membrane ERs. In addition, mutation of the palmitoylation site on estrogen receptor (ER) α blocks ERα-mediated cAMP response element-binding protein phosphorylation. Similar results were obtained after mutation of the palmitoylation site on ERβ. Importantly, mutation of either ERα or ERβ did not affect the ability of the reciprocal ER to signal at the membrane. In contrast, membrane ERα and ERβ signaling were both dependent on the expression of the palmitoylacyltransferase proteins DHHC-7 and DHHC-21. Neither mGluR activity nor caveolin or ER expression was affected by knockdown of DHHC-7 and DHHC-21. These data collectively suggest discrete mechanisms that regulate specific isoform or global membrane ER signaling in neurons separate from mGluR activity or nuclear ER function.

Repeated activation of the mesolimbic dopamine system results in persistent behavioral alterations accompanied by a pattern of neural plasticity in the nucleus accumbens (NAc). As the accumulation of the transcription factor FosB may be an important component of this plasticity, the question addressed in our research is whether FosB is regulated by sexual experience in females. We have shown that female Syrian hamsters, given sexual experience, exhibit several behavioral alterations including increased sexual efficiency with naïve male hamsters, sexual reward and enhanced responsive- Experience with drugs of abuse, motivated behaviors, wheel running behavior or instrumental learning results in the activation of the mesolimbic dopamine system and persistent alterations in the nucleus accumbens (NAc) (Becker et al.

Estrogens affect cerebellar activity and cerebellum-based behaviors. Within the adult rodent cerebellum, the best-characterized action of estradiol is to enhance glutamatergic signaling. However, the mechanisms by which estradiol promotes glutamatergic neurotransmission remain unknown. Within the mouse cerebellum, we found that estrogen receptor activation of metabotropic glutamate receptor type 1a strongly enhances neurotransmission at the parallel fiber-Purkinje cell synapse. The blockade of local estrogen synthesis within the cerebellum results in a diminution of glutamatergic neurotransmission. Correspondingly, decreased estrogen availability via gonadectomy or blockade of aromatase activity negatively affects locomotor performance. These data indicate that locally derived, and not just gonad-derived, estrogens affect cerebellar physiology and function. In addition, estrogens were found to facilitate parallel fiber-Purkinje cell synaptic transmission in both sexes. As such, the actions of estradiol to support cerebellar neurotransmission and cerebellum-based behaviors might be fundamental to understanding the normal processing of activity within the cerebellar cortex.

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