This is an intriguing possibility since GABA activity can be excit atory during development. Excitatory GABAergic signaling sellekchem has already been proposed as a contributor to the pathophysiology of epilepsy. Persistent altera tions in inhibitory balance after TBI have been implicated in increased post injury development of epilepsy and in cognitive memory deficits. Inhibitors,Modulators,Libraries Just as different subunits have unique effects on GABA A function, their differential alteration following TBI can have specific implications for the pathophysiological state of the recovering brain. Thompson et al. demon strated differential mRNA changes for GABAAR subunits in cultured cerebellar granule cells exposed to protein kinase A. Protein kinase A inhibitors prevented these effects on 1 but not on 6, indicating differential regula tory mechanisms for different subunits.

Epilepsy research has also demonstrated disparate alterations in subunits. Although B3 mRNA decreased in the hippocampus fol lowing kainic acid induced seizures, 1 mRNA increased in the interneurons of the dentate gyrus and CA3. Inhibitors,Modulators,Libraries Huopaniemi et al. demonstrated more than 130 tran scriptional changes in 2, 3, and 5 in 1 point mutated mice after Inhibitors,Modulators,Libraries a single DZ injection, although there was no effect in wild type mice. Therefore, in the absence of spe cific 1 genes, other subunit transcripts changed, indi cating a complicated compensatory relationship among subunits. The 1 subunit was the only one to demonstrate signif icant changes at every time point studied. This is impor tant because 1 may mediate apoptosis via the endoplasmic reticulum stress pathway.

Since the cells in the current study were lysed to obtain whole protein measures, regional specificity of each protein cannot be determined and therefore the changes may also represent subunits in the ER. Overexpression of 1 may be related to apoptotic processes after TBI. Also, 1 over expression can trigger apoptosis due to a complicated relationship with Inhibitors,Modulators,Libraries c myc, a proto oncogene that regulates cellular proliferation and apoptosis. The 1 gene is a direct target for suppression by c myc and mRNA expres sion is inversely related to c myc expression. This inverse balance between c myc and 1 may be either a marker or a key player in the developmental cessation of neuronal pruning. Shifts in c myc expression during neuronal insult such as TBI may result in changes to the 1 gene, independent of its role in GABAAR function.

Over expression of 1 has also been associated with apoptosis in a Ca2 dependent manner. Specifically, disruption of ER Ca2 balance may alter 1 mRNA, producing an increase that activates Inhibitors,Modulators,Libraries caspase 3 and induces apoptosis. Therefore, blocking Ca2 influx due to TBI may pre vent 1 associated apoptosis by preventing significant Rapamycin mTOR increases in 1 subunit proteins.