Electrophysiologists explore underlying physiology and new treatments for learning disabilities

New research published in the Journal of Physiology is helping to move us closer to developing a targeted and reliable class of drugs for limiting learning disabilities in individuals with X-linked mental retardations.

Researchers from the University of Birmingham and the Institut Cochin in Paris have collaborated on a study of the pathophysiology of non-specific X-linked mental retardation. X-linked mental retardations (XLMR disorders) result from a single gene mutation and are typically characterised by moderate to severe cognitive impairments, usually affecting males more severely. Although existing studies support the idea that dendritic shape and structure are crucial in determining the cellular mechanisms for these disorders, researchers are keen to extend their understanding to include how the physiological consequences result in cognitive impairment and possible treatments for this.

The Oligophrenin-1 protein is crucial to the morphogenesis of dendritic spines and it's absence is known to result in compromised neuronal function. Billuart et al (2007) created a mouse model of XLMR disorders based on mutation of the Ophn-1 gene which codes for the oligophrenin-1 protein. In the present study Powell et al combined in-vitro electrophysiology recordings from granule cells in the dentate gyrus of the hippocampus, with Z-stack imaging to explore the physiological mechanisms that present in these disorders and cause learning disabilities. They made whole-cell patch-clamp recording using NPI- SEC10L amplifier and dendritic spine/tree analysis was achieved using an Olympus FV1000 confocal microscope.

They confirmed that individuals with reduced expression of the Ophn-1 gene had disrupted spine morphology including "reduced dendritic tree complexity and mature dendritic spine density". The lower density of spines was accompanied by reduced excitatory neurotransmitter release and smaller maximum excitatory postsynaptic currents (ESPCs). Brain rythyms that have a key role in cognitive processes are dependent on repetitive firing of inhibitory interneurons. Similar to excitatory transmission, inhibitory postsynaptic currents (IPSC's) were smaller in Oligophrenin-1 null mice. A key observation was that inhibitory synapses have a smaller readily releasable pool of synaptic vesicles resulting in an inability to maintain neurotransmission at frequencies necessary for generation of brain rythyms. This observation suggests a potential mechanism to explain the cognitive deficits.

Re-dressing the careful balance between excitatory and inhibitory firing of synapses is crucial to achieving normal brain function and key to identifying possible pharmacological methods for treatment of learning disabilities. The team demonstrated that Y-27632,a drug known as a rho-GAP inhibitor, reversed the altered neurotransmission, but not the structural abnormalities of dendrites, within 20 minutes; these results offers an interesting route for further studies of pharmacological treatment for learning disabilities.

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

Powell AD, Gill KK, Saintot PP, Jiruska P, Chelly J, Billuart P, Jefferys JG.

J Physiol. 2011 Nov 28. [Epub ahead of print]

PMID: 22124149