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

Eur J Neurosci. 1998 Jan;10(1):377-87. doi: 10.1046/j.1460-9568.1998.00019.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / enzymology
  • Brain-Derived Neurotrophic Factor / genetics*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Epilepsy / physiopathology*
  • Exons / physiology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Male
  • Nerve Growth Factors / genetics
  • Promoter Regions, Genetic / physiology
  • Proto-Oncogene Proteins c-fos / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Brain-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases