Gene expression profile of neurodegeneration induced by [alpha] sub(1B)-adrenergic receptor overactivity: NMDA/GABA sub(A) dysregulation and apoptosis

The [alpha] sub(1)-adrenergic receptors ([alpha] sub(1)ARs) play an important role in mediating sympathetic neurotransmission in peripheral organ systems; however, central [alpha] sub(1)ARs are not well characterized. Additionally, due to the lack of sufficiently subtype-selective drugs or high avidity antibodies, the contribution of each [alpha] sub(1)AR subtype to various central functions is currently unclear. Transcription regulation through [alpha] sub(1)AR subtypes in the CNS is also unknown. Of interest, transgenic mice that systemically overexpress the [alpha] sub(1B)AR show central symptoms that include age- progressive impaired mobility, neurodegeneration and susceptibility to epileptic seizure. To investigate the molecular basis of this phenotype, oligonucleotide microarray studies of whole brains of various ages were carried out to compare gene expression profiles between transgenic and normal brains. The results indicated changes in expression of apoptotic, calcium regulatory, neurodegenerative and genes involved in neurotransmission. Defects in regulation of intracellular calcium are known to play a role in cell death; thus, these genes may provide clues as to the molecular basis of [alpha] sub(1B)AR-induced neurodegeneration. Epilepsy is a disorder that can be caused by an imbalance between excitatory (e.g. glutamate) and inhibitory (e.g. GABA) signals. Microarray analysis of transgenic brains showed increased N-methyl-D-aspartate (NMDA) receptors and decreased GABA sub(A), which were confirmed with immunohistochemistry, western blot and radioligand binding studies. The [alpha] sub(1B)AR also co-localized with the glutamatergic distribution, suggesting a glutamate imbalance as a molecular rationale for the epileptic seizures.