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Abstract
Intellectual disability affects 2–3% of the population; mutations of the X-chromosome are a major cause of moderate to severe cases. The link between the molecular consequences of the mutation and impaired cognitive function remains unclear. Loss of function mutations of oligophrenin-1 (OPHN1) disrupt Rho-GTPase signalling. Here we demonstrate abnormal neurotransmission at CA3 synapses in hippocampal slices from Ophn1-/y mice, resulting from a substantial decrease in the readily releasable pool of vesicles. As a result, synaptic transmission fails at high frequencies required for oscillations associated with cognitive functions. Both spontaneous and KA-induced gamma oscillations were reduced in Ophn1-/y hippocampal slices. Spontaneous oscillations were rapidly rescued by inhibition of the downstream signalling pathway of oligophrenin-1. These findings suggest that the intellectual disability due to mutations of oligophrenin-1 results from a synaptopathy and consequent network malfunction, providing a plausible mechanism for the learning disabilities. Furthermore, they raise the prospect of drug treatments for affected individuals.
Original language | English |
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Article number | e95871 |
Journal | PLoS ONE |
Volume | 9 |
Issue number | 5 |
DOIs | |
Publication status | Published - 6 May 2014 |
Keywords
- Disabilities
- Gamma spectrometry
- Genetic oscillators
- Mutation
- Neurons
- Neurotransmission
- Synapses
- Vesicles
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- 1 Finished
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Pathophysiology of a Mouse Model of X-Linked Mental Retardation
Jefferys, J.
31/08/05 → 30/08/08
Project: Research