Attenuation of the seizure‐induced expression of BDNF mRNA in adult rat brain by an inhibitor of calcium/calmodulin‐dependent protein kinases

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Abstract
We have examined the potential involvement of calcium/calmodulin‐dependent protein kinases in the regulation of brain‐derived neurotrophic factor mRNA in vivo following kainic acid (kainate)‐induced seizure activity by in situ hybridization. KN‐62, a specific inhibitor of calcium/calmodulin‐dependent protein kinase type II and IV, blocked the characteristic induction of brain‐derived neurotrophic factor mRNA seen following seizure activity. This blockade was specific to calcium/calmodulin‐dependent protein kinase type II and IV as inhibitors of both protein kinase C and cAMP‐dependent protein kinase had no effect. Inhibition of brain‐derived neurotrophic factor mRNA increases varied between brain regions; an almost complete inhibition was seen throughout cortical regions, whereas only partial inhibitory effects were noted within hippocampus. A similar inhibition of increased c‐fos mRNA was observed throughout cortical, hippocampal and diencephalic regions. The two predominant brain‐derived neurotrophic factor transcripts induced by kainate, containing exons I or III, were differentially affected by KN‐62. The cortical induction of exon I was blocked by KN‐62, whereas exon III was not, providing additional evidence for the differential regulation of individual brain‐derived neurotrophic factor transcripts and demonstrating that inhibition of brain‐derived neurotrophic factor induction was not due to general blockade of seizure activity throughout the neocortex. These data implicate calcium/calmodulin‐dependent protein kinase type II or IV in the regulation of brain‐derived neurotrophic factor mRNA in vivo and suggest regionally specific mechanisms occur throughout the brain.