Rapid Reversal of Impaired Inhibitory and Excitatory Transmission but Not Spine Dysgenesis in a Mouse Model of Mental Retardation

J Physiol. 2012 Feb 15;590(4):763-76. doi: 10.1113/jphysiol.2011.219907. Epub 2011 Nov 28.

Abstract

Intellectual disability affects 2-3% of the population: those due to mutations of the X-chromosome are a major cause of moderate to severe cases (1.8/1000 males). Established theories ascribe the cellular aetiology of intellectual disability to malformations of dendritic spines. Recent work has identified changes in synaptic physiology in some experimental models. Here, we investigated the pathophysiology of a mouse model of intellectual disability using electrophysiological recordings combined with confocal imaging of dentate gyrus granule neurons. Lack of oligophrenin-1 resulted in reductions in dendritic tree complexity and mature dendritic spine density and in evoked and spontaneous EPSCs and IPSCs. In the case of inhibitory transmission, the physiological change was associated with a reduction in the readily releasable pool and vesicle recycling which impaired the efficiency of inhibitory synaptic transmission. Acute inhibition of the downstream signalling pathway of oligophrenin-1 fully reversed the functional changes in synaptic transmission but not the dendritic abnormalities. The impaired inhibitory (as well as excitatory) synaptic transmission at frequencies associated with cognitive function suggests a cellular mechanism for the intellectual disability, because cortical oscillations associated with cognition normally depend on inhibitory neurons firing on every cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / therapeutic use
  • Animals
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / physiology*
  • Dendritic Spines / drug effects
  • Dendritic Spines / pathology*
  • Dendritic Spines / physiology
  • Dentate Gyrus / physiology
  • Disease Models, Animal
  • Enzyme Inhibitors / therapeutic use
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / physiology*
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology*
  • Intellectual Disability / drug therapy
  • Intellectual Disability / pathology
  • Intellectual Disability / physiopathology*
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Patch-Clamp Techniques
  • Pyridines / therapeutic use
  • Synaptic Transmission / physiology
  • rho-Associated Kinases / antagonists & inhibitors

Substances

  • Amides
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • GTPase-Activating Proteins
  • Nuclear Proteins
  • Ophn1 protein, mouse
  • Pyridines
  • Y 27632
  • rho-Associated Kinases