Prolonged Type 1 Metabotropic Glutamate Receptor Dependent Synaptic Signaling Contributes to Spino-Cerebellar Ataxia Type 1

J Neurosci. 2016 May 4;36(18):4910-6. doi: 10.1523/JNEUROSCI.3953-15.2016.

Abstract

Type 1 metabotropic glutamate receptor (mGluR1)-dependent signaling at parallel fiber to Purkinje neuron synapses is critical for cerebellar function. In a mouse model of human spino-cerebellar ataxia type 1 (early SCA1, 12 weeks) we find prolonged parallel fiber mGluR1-dependent synaptic currents and calcium signaling. Acute treatment with a low dose of the potent and specific activity-dependent mGluR1-negative allosteric modulator JNJ16259685 shortened the prolonged mGluR1 currents and rescued the moderate ataxia. Our results provide exciting new momentum for developing mGluR1-based pharmacology to treat ataxia.

Significance statement: Ataxia is a progressive and devastating degenerative movement disorder commonly associated with loss of cerebellar function and with no known cure. In the early stages of a mouse model of human spinocerebellar ataxia type 1, SCA1, where mice exhibit only moderate motor impairment, we detect excess "gain of function" of metabotropic glutamate receptor signaling at an important cerebellar synapse. Because careful control of this type of signaling is critical for cerebellar function in mice and humans, we sought to remove the excess signaling with a powerful, readily available pharmacological modulator. Remarkably, this pharmacological treatment acutely restored normal motor function in the ataxic mice. Our results pave the way for exploring a new avenue for early treatment of human ataxias.

Keywords: ataxia; calcium; cerebellum; mGluR1; parallel fibers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Calcium Signaling / physiology
  • Female
  • Male
  • Mice
  • Movement / drug effects
  • Purkinje Cells / metabolism
  • Quinolines / pharmacology
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, Metabotropic Glutamate / genetics*
  • Receptors, Metabotropic Glutamate / metabolism
  • Signal Transduction* / drug effects
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / physiopathology*
  • Spinocerebellar Ataxias / psychology
  • Synapses* / drug effects

Substances

  • (3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone
  • Quinolines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1