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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.

Original publication

DOI

10.1113/jphysiol.2011.219907

Type

Journal article

Journal

J Physiol

Publication Date

15/02/2012

Volume

590

Pages

763 - 776

Keywords

Amides, Animals, Cytoskeletal Proteins, Dendritic Spines, Dentate Gyrus, Disease Models, Animal, Enzyme Inhibitors, Excitatory Postsynaptic Potentials, GTPase-Activating Proteins, In Vitro Techniques, Inhibitory Postsynaptic Potentials, Intellectual Disability, Mice, Nuclear Proteins, Patch-Clamp Techniques, Pyridines, Synaptic Transmission, rho-Associated Kinases