Local Estrogen Synthesis Regulates Parallel Fiber–Purkinje Cell Neurotransmission Within the Cerebellar Cortex

Abstract

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.

Mechanisms for estrogen receptor expression in human cancer

“…Although 17-β-estradiol inhibits T and B cell development, it enhances B cell function in ERα-dependent manner, involving both genomic and non-genomic ER signaling in B lymphocytes [ 39 , 40 ]. Moreover, the brain of both sexes is a major target of estradiol and a site of estrogen synthesis [ 41 , 42 ]. ERβ is a dominant ER subtype in the adult cerebellum.…”

De Novo Synthesized Estradiol: A Role in Modulating the Cerebellar Function

“…Nevertheless, the age-related maintenance of a low level of aromatase expression in the cerebellum seems to have a cardinal physiological significance in the contribution of controlling the cerebellar function. Recent reports showed that nE2 synthesis rapidly influences the glutamatergic transmission between the parallel fibers and Purkinje cells in the cerebellar cortex and acutely impact cerebellar dependent behaviors in adult rodents [39,40,74,87]. Furthermore, the high level of estrogen receptors found in the cerebellum of adults is supportive of cerebellar responsiveness even to a minute and localized nE2 synthesis [88][89][90].…”

“…Experiments conducted in the brainstem and cerebellum indicate that despite the supposed low synthesis in the experimental models used, nE2 may contribute to rapidly modulating neurotransmission via dynamic change of its availability at a synaptic level [38][39][40][41][42]. It has already been demonstrated that modifications in local estradiol synthesis may be achieved by changes in aromatase activity.…”

Targeted sequencing of the LRRTM gene family in suicide attempters with bipolar disorder

“…More recently, estrogen was shown to increase the expression of glutamate receptor GluR1 and increase spine density and glutamatergic synapse formation in both PFC and superficial superior colliculus neurons (Khan, Dhandapani, Zhang, & Brann, ). Further, estrogen has been demonstrated to regulate neurotransmission in the cerebellum and increase glutamatergic synaptic transmission in the hippocampus, but through different mechanisms in males and females (Hedges et al, ; Oberlander & Woolley, ). This sex‐specific difference highlights how the same functional endpoint can be achieved in a cell through different pathways, and that the functional endpoint can be perturbed differently based on sex.…”