The AMPA class of glutamate receptors mediate the majority of excitatory neurotransmission in the brain. These receptors are specifically implicated in the propagation of seizure activity. One member of the AMPA receptor family, the GluR2 subunit, dominates connections between excitatory neurons in the mature neocortex. The absence of this subunit alters the properties of AMPA receptors such that they become impermeable to calcium ions and show use-dependent facilitation. Down-regulations in GluR2 have been noted in a number of animal epilepsy models and in human epilepsy. This laboratory has recently demonstrated that GluR2 is functionally expressed in pyramidal neuron synaptic receptors at very low levels early in rat neocortical development. Thus it appears that in epileptic cortex there may be a recapitulation of the early postnatal phenotype of GluR2-lacking receptors, which are hypothesized to be epileptogenic in adult brain. In this proposal, whole cell voltage-clamp techniques and laser-scanning caged-glutamate photolysis will be used with rat neocortical brain slices to test the generality of the finding regarding developmental GluR2 alterations in pyramidal neurons of different cortical regions and lamina. Further, the functional consequence regarding the ability of excitatory synaptic circuits to sustain repetitive, seizure-like activity will be examined. The hypothesis will be tested that decreased expression of GluR2 subunits in epileptic tissue results in a functional alteration in the synaptic receptors that would allow for increased calcium entry and post-synaptic facilitation, both of which may be important in the development of epilepsy.
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