Fragile X syndrome in development of the somatosensory cortex
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Integrative Physiology
Abstract
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Technical Summary
Fragile X syndrome (FXS) is the commonest genetically inherited form of mental retardation. Sufferers display impaired development of cognitive function including defects in sensory processing. Higher cognitive functions such as those affected by FXS are carried out in the cerebral cortex. I will use the rodent barrel cortex, a region which carries out sensory processing, as a model of cortical development, together with a genetic mouse model of FXS developed in Edinburgh, to establish the defects in development of synaptic and cellular physiology which lead to the symptoms of FXS.
Multidisciplinary research on the barrel cortex system has shown that plastic changes in thalamocortical synapses, which can be studied using in vitro electrophysiology, are the same as the processes responsible for experience-dependent development of sensory processing. In adults this sensory processing allows input from the whiskers, which reaches the barrel cortex via synapses in the brainstem and thalamus, to determine the location, size and texture of objects detected by the whiskers. I have shown previously that long-term synaptic plasticity of excitatory transmission and developmental recruitment of a specific class of inhibitory interneuron act together to change a juvenile physiological phenotype in to a mature phenotype ideally suited to information processing. Disruption of these processes could lead to cognitive problems such as those seen in FXS.
At present, however, it is unclear how these synaptic plasticity phenomena are induced in vivo and what role the juvenile physiological phenotype, including slow kainate receptor-mediated synaptic transmission, may have in this induction. The role of the other classes of inhibitory interneurons present in the barrel cortex is also unknown. I will use in vitro electrophysiology in the thalamocortical slice preparation to determine whether a prominent form of network activity recorded in juvenile barrel cortex in vivo, the spindle burst, is able to produce the depolarization needed to induce long-term synaptic plasticity. I will use kainate receptor knock-out mice to test the role of these receptors in spindle bursts and induction of plasticity. I will use mice which express GFP in interneurons (GAD-65 GFP mice) to elucidate which other classes of interneuron are recruited by physiologically relevant bursts of thalamic activity and how this affects the function of the network. Finally I will use a mouse model of FXS to show whether defects in these processes lead to mental retardation in FXS. Understanding these defects may lead to treatments for this condition.
Multidisciplinary research on the barrel cortex system has shown that plastic changes in thalamocortical synapses, which can be studied using in vitro electrophysiology, are the same as the processes responsible for experience-dependent development of sensory processing. In adults this sensory processing allows input from the whiskers, which reaches the barrel cortex via synapses in the brainstem and thalamus, to determine the location, size and texture of objects detected by the whiskers. I have shown previously that long-term synaptic plasticity of excitatory transmission and developmental recruitment of a specific class of inhibitory interneuron act together to change a juvenile physiological phenotype in to a mature phenotype ideally suited to information processing. Disruption of these processes could lead to cognitive problems such as those seen in FXS.
At present, however, it is unclear how these synaptic plasticity phenomena are induced in vivo and what role the juvenile physiological phenotype, including slow kainate receptor-mediated synaptic transmission, may have in this induction. The role of the other classes of inhibitory interneurons present in the barrel cortex is also unknown. I will use in vitro electrophysiology in the thalamocortical slice preparation to determine whether a prominent form of network activity recorded in juvenile barrel cortex in vivo, the spindle burst, is able to produce the depolarization needed to induce long-term synaptic plasticity. I will use kainate receptor knock-out mice to test the role of these receptors in spindle bursts and induction of plasticity. I will use mice which express GFP in interneurons (GAD-65 GFP mice) to elucidate which other classes of interneuron are recruited by physiologically relevant bursts of thalamic activity and how this affects the function of the network. Finally I will use a mouse model of FXS to show whether defects in these processes lead to mental retardation in FXS. Understanding these defects may lead to treatments for this condition.