Rapid reversal of impaired inhibitory and excitatory transmission but not spine dysgenesis in a mouse model of mental retardation

Abstract

Non-technical summary Intellectual disability has long been attributed at the cellular level to abnormalities in the structures that receive incoming connections to the major classes of neurons in the brain. These misshaped 'dendrites' and especially misshaped 'dendritic spines' have been found in many types of intellectual disability. We have used a mouse model of one of the human intellectual disability mutations on a gene on the X-chromosome called Ophn-1. We show that, in addition to the misshaped dendritic spines, these mice have abnormal physiology in the inability of both excitatory and inhibitory inputs ('synapses') to operate repetitively as they need to in many aspects of normal brain function. A drug known as a Rho-GAP inhibitor was able to reverse the physiological impairment within 20 min, without changing the structure of dendrites or dendritic spines. This class of drug may have a role in limiting disability in this condition.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. Abbreviations IEI, interevent interval; RRP, readily releasable pool; XLMR, X-linked mental retardation.

Reduced Gamma Oscillations in a Mouse Model of Intellectual Disability: A Role for Impaired Repetitive Neurotransmission?

“…We have previously demonstrated that repetitive inhibitory neurotransmission onto dentate gyrus granule neurons is reduced due to a smaller RRP [4]. We first tested whether the central conclusions from dentate granule cells generalised to CA3 pyramidal neurons.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…The role of oligophrenin1 has been confirmed in vivo; knockout Ophn1 -/y mice present a decreased complexity of the dendritic tree together with a reduction in the density of mature dendritic spines 259 . These animals also exhibit a decreased adult neurogenesis.…”

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

“…Lack of OPHN1 was associated with a decrease in cellular endocytosis which was efficiently reversed by ROCK antagonist, suggesting that this cascade may participate in the pathophysiology of CD associated with Ophn1 mutations. As expected from a general blockade of membrane trafficking, both membranous diffusion of postsynaptic [13 -15] and presynaptic vesicular trafficking [13,16] were affected in neuronal cells in which acute or permanent deletions of Ophn1 were introduced, suggesting important pre-and postsynaptic functions for OPHN1.…”