Estradiol Triggers Cerebellar MLI-PC LTP via ERβ/Protein Kinase C Signaling Cascades in Mice In Vivo

TL;DR

Estradiol activates ERβ and PKC signaling to trigger synaptic strengthening in mouse cerebellum, blocking a different form of synaptic weakening.

Contribution

This study reveals a novel estradiol-ERβ-PKC signaling pathway that induces cerebellar synaptic plasticity in vivo.

Findings

Estradiol prevents LTD and induces LTP at MLI-PC synapses via ERβ activation.

Estradiol-induced LTP is mediated by PKC and intracellular Ca²⁺, not protein kinase A.

ERβ is abundantly expressed on Purkinje cell dendrites and somas in the Crus II region.

Abstract

17β-estradiol (E2) enhances the cerebellar molecular layer interneurons (MLIs)—Purkinje cells (PCs) synaptic transmission via activation of the Erβ in vivo in mice. Whether E2 regulates cerebellar MLI-PC synaptic plasticity is unknown. To investigate the mechanism of E2, we evaluated the modulation of facial stimulation-evoked MLI-PC long-term plasticity in mice. Cell-attached recordings from PCs of Crus II were performed using an Axopatch-700B patch-clamp amplifier. The MLI-PC synaptic transmission was evoked by facial stimulation. Immunohistochemistry was used to detect the expression of ERβ. Under control conditions, 1 Hz facial stimuli induced long-term depression (LTD) at MLI-PC synapses, characterized by a sustained reduction in P1 amplitude and a simple spike (SS) pause. The facial stimulus-induced MLI-PC LTD was completely prevented by E2, but this effect was reversed by a selective ERα/ERβ antagonist, ICI182780. Blockade of cannabinoid receptor 1 (CB1R) eliminated the MLI-PC LTD under control conditions, but revealed an E2-triggered long-term potentiation (LTP). The E2-triggered MLI-PC LTP persisted in the presence of an ERα antagonist but was absent in the presence of an ERβ antagonist PHTPP. The E2-triggered MLI-PC LTP remained unaffected by protein kinase A inhibition but was abolished by inhibition of protein kinase C (PKC) and intracellular Ca2+ depletion. Moreover, ERβ immunoreactivity was abundantly distributed around dendrites and somas of PCs in the Crus II region of the mouse cerebellar cortex. The present results suggest that E2 activates ERβ, thereby triggering facial stimulation-induced MLI-PC LTP via the PKC signaling cascade, which occludes CB1R-dependent MLI-PC LTD in the cerebellar cortex of mice in vivo.

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