mGluR1/IP3/ERK signaling pathway regulates vestibular compensation in ON UBCs of the cerebellar flocculus

Abstract

AimsTo investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal‐regulated kinase (ERK) signaling pathway.MethodsFirst, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)‐3,5‐dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p‐ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p‐ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC‐related behavior was observed.ResultsmGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p‐ERK1/2 levels, while LY367385 group showed a decrease in PI and p‐ERK1/2 levels in cerebellar UBC of rats. The western blot results of p‐ERK and total ERK confirm and support the observations. DHPG alleviated VC‐related behavior phenotypes, while LY367385 exacerbated vestibular decompensation‐like behavior induced by UL.ConclusionmGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.

Molecular profile of vestibular compensation in the medial vestibular nucleus after unilateral labyrinthectomy

“…Experimental rats were anesthetized with sodium pentobarbital (40 mg/kg, intraperitoneal injection) and subjected to unilateral labyrinthectomy (UL) of the right ear as previously described. 3 , 13 , 14 , 15 The surgical procedure was performed under the operating microscope. Firstly, a 1.5 cm‐long skin incision was made behind the right external acoustic meatus; the cervical muscles, posterior belly of the digastric muscle, the stylohyoid, and their nerves were spared.…”

“…Experimental rats were anesthetized with sodium pentobarbital (40 mg/kg, intraperitoneal injection) and subjected to unilateral labyrinthectomy (UL) of the right ear as previously described 3,13–15 . The surgical procedure was performed under the operating microscope.…”