title: Rapid reversal of impaired inhibitory and excitatory transmission but not spine dysgenesis in a mouse model of mental retardation.
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.
authors: School of Clinical and Experimental Medicine (Neuronal Networks Group), College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Andrew D
authors: AD
authors: Powell
authors: Kalbinder K
authors: KK
authors: Gill
authors: Pierre-Philippe
authors: PP
authors: Saintot
authors: Premysl
authors: P
authors: Jiruska
authors: Jamel
authors: J
authors: Chelly
authors: Pierre
authors: P
authors: Billuart
authors: John G R
authors: JG
authors: Jefferys
mesh_terms: D000577:Amides / Q000627:therapeutic use; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D018891:Dentate Gyrus / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008607:Intellectual Disability / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases