title: Reduced gamma oscillations in a mouse model of intellectual disability: a role for impaired repetitive neurotransmission?
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.
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Powell
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Pierre-Philippe
authors.initials: PP
authors.lastname: Saintot
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Kalbinder K
authors.initials: KK
authors.lastname: Gill
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ashtami
authors.initials: A
authors.lastname: Bharathan
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: S Caroline
authors.initials: SC
authors.lastname: Buck
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Morris
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; Department of Developmental Epileptology, Institute of Physiology, Academy of Sciences of Czech Republic, Prague, Czech Republic; Department of Neurology, Charles University, 2nd School of Medicine, Prague, Czech Republic.
authors.forename: Premysl
authors.initials: P
authors.lastname: Jiruska
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: John G R
authors.initials: JG
authors.lastname: Jefferys
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D065818:Gamma Rhythm; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics; D009435:Synaptic Transmission
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse