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.

Altered thalamocortical development in the SAP102 knockout model of intellectual disability

“…In addition to SAP102, mutations in many other synaptically expressed proteins lead to ID and ASD ( 3 , 4 ). Consistent with our findings of reduced TC connectivity mutations or loss of many of these proteins also result in reductions in glutamatergic synapse number or excitatory drive including SHANK 3 ( 34 ), MeCP2 ( 35 ) and oligophrenin 1 ( 36 ); the latter two, like SAP102, encoded by X-lined genes. In our study this reduction in TC connectivity is preceded by altered synaptic function in early life suggesting a mechanism for the widely observed reductions of long-range connectivity observed in patients with ASD ( 37 ).…”

ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability

“…Ophn1 encodes for a Rho GTPase activating protein (RhoGAP) which negatively regulates Rac, RhoA and Cdc42 (Billuart et al, 1998;Fauchereau et al, 2003;Khelfaoui et al, 2007). Ophn1 is expressed in several brain regions, including the cerebral cortex and the hippocampus, where it contributes to synapse maturation and plasticity (Govek et al, 2004;Khelfaoui et al, 2007;Powell et al, 2012;Powell et al, 2014). Ophn1 knock-out (KO) mice represent an excellent model of Ophn1 mutations in humans (Khelfaoui et al, 2007).…”

“…At the electrophysiological level, the loss of function of Ophn1 leads to alterations of both excitatory and inhibitory synaptic transmission. Patch-clamp recordings from the hippocampus of Ophn1 KO mice have shown reductions in evoked and spontaneous excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs;Powell et al, 2012Powell et al, , 2014. By contrast, the Ophn1 deficiency leads to an increased spontaneous activity in the medial prefrontal cortical (mPFC) neurons, where Zhang and coworkers (2017) found a higher frequency of excitatory postsynaptic potentials (EPSPs).…”

Dopamine D3 Receptors Inhibit Hippocampal Gamma Oscillations by Disturbing CA3 Pyramidal Cell Firing Synchrony

“…Gamma band (30–90 Hz) oscillations have been implicated in a range of aforementioned cognitive processes ( Axmacher et al, 2010 ; Powell et al, 2014 ) and are known to be generated by the synchronous firing of perisomatic parvalbumin containing fast-spiking basket cells ( Gulyás et al, 2010 ). An increasing number of studies have demonstrated that gamma oscillations are altered and instable in schizophrenic patients and have led to the hypothesis that disturbances in gamma band network activity may be involved in the pathophysiology of the disease ( Uhlhaas and Singer, 2010 ).…”