After ischemia expression of transcription

After ischemia, expression of transcription factors, including products of immediate early genes, stress proteins and neurotrophic factors are also altered in CA1 neurons78, 79. These proteins are potential candidates for downregulating of GluR2 expression by reducing mRNA transcription or stability, or both. Since some mRNAs and proteins are upregulated, the decrease in GluR2 is not simply due to a loss of transcriptional or translational capability but appears to result from a regulatory, although maladaptive mechanism. Increased Ca2+ influx through GluR2-less AMPA receptors in response to endogenous glutamate is then expected to lead to oxidative stress and activation of apoptotic genes resulting in delayed post-ischemic neurodegeneration.
In adult rats, kainate-induced status epilepticus leads to delayed neurodegeneration of CA3 hippocampal pyramidal cells[80]. Kainic Tyrphostin 9 (administered i.p. or injected directly into the amygdala) leads to downregulation of GluR2 in the vulnerable CA3 region at times preceding significant cell loss66, 81. GluR3 is also reduced in the CA3 subfield, but to a lesser degree. gluR1 and nr1 mRNA expression are unchanged[81]. As in global ischemia, these changes in GluR expression would be expected to lead to increased Ca2+ influx through AMPA receptors which could cause the subsequent cell death. In support of this idea, transgenic mice heterozygous for a gluR2 allele that is not edited at the Q/R site express Ca2+-permeable AMPA receptors in principal neurons[43]. The mutant mice develop recurrent seizures and die by three weeks of age. Postmortem histology reveals selective neurodegeneration in the hippocampal CA3 but not CA1 region. The CA1 neurons may survive for the same reason they survive in gluR2 knockout mice, whereas CA3 neurons may die because of involvement in seizures. Interestingly, GluR2 expression is not reduced in the hippocampus of young rats, at ages at which kainate induces status epilepticus without subsequent CA3 cell loss (L.K. Friedman, E.F. Sperber, S.L. Moshé, M.V.L. Bennett and R.S. Zukin, unpublished observations). Together, these findings implicate the regulation of GluR2 expression in the delayed neurodegeneration following kainate-induced status epilepticus, and suggest the possibility that AMPA receptor antagonists could afford protection against seizure-induced damage[82].
Concluding remarks This article reviews evidence that severe neurological insults such as global ischemia and limbic seizures trigger a `molecular switch' that shuts off gluR2 AMPA receptor gene expression in cells destined to die. The GluR2 hypothesis predicts that Ca2+ entry through GluR2-lacking AMPA receptors in neurons that normally express Ca2+-impermeable channels contributes to or causes delayed cell death in response to en- dogenous glutamate. In addition to their role in neurological disorders, Ca2+-permeable AMPA receptors are thought to serve a number of physiological functions, including strengthening of synaptic transmission in certain spinal neurons[83], activation of Ca2+-dependent K+ channels and inactivation of NMDA receptors (see 30, 31). Increased Ca2+ permeation through AMPA receptors may also be involved in the development of kindled seizures[84]. The underlying mechanism by which Ca2+ permeability is increased is, in all physiological and pathological cases reported to date, a reduction in gluR2 gene expression rather than decreased editing at the Q/R site11, 70, 71, 72, 85. Reduction in GluR2 expression has also been observed in other vulnerable neuronal populations including cerebellar Purkinje and granule cells in mutant spastic rats[86], pyramidal cells of the parahippocampal gyrus in schizophrenia[87], and spinal motor neurons in amyotrophic lateral sclerosis[88]. These examples indicate the more general applicability of the GluR2 hypothesis to other neuropsychiatric diseases and disorders involving glutamate-induced cell death (see Table 1). If the underlying mechanism is proven correct, there is promise in the development of antagonists specific for AMPA receptors, in particular those that are Ca2+-permeable, for intervention in the neurodegeneration associated with human disorders such as stroke and epilepsy.