Elsevier

Experimental Neurology

Volume 149, Issue 1, January 1998, Pages 161-174
Experimental Neurology

Regular Article
BDNF Restores the Expression of Jun and Fos Inducible Transcription Factors in the Rat Brain Following Repetitive Electroconvulsive Seizures

https://doi.org/10.1006/exnr.1997.6686Get rights and content

Abstract

The expression of inducible transcription factors was studied following repetitive electroconvulsive seizures (ECS). c-Fos, c-Jun, JunB, and JunD immunoreactivities were investigated following a single (1× ECS) or repetitive ECS evoked once per day for 4, 5, or 10 days (4×ECS, 5×ECS, or 10×ECS). Animals were killed 3 or 12 h following the last ECS. Three hours after 1×ECS, c-Fos was expressed throughout the cortex and hippocampus. After 5×ECS and 10×ECS, c-Fos was reexpressed in the CA4 area, but was completely absent in the other hippocampal areas and cortex. In these areas, c-Fos became only reinducible when the time lag between two ECS stimuli was 5 days. In contrast to c-Fos, intense JunB expression was inducible in the cortex and hippocampus, but not CA4 subfield, after 1×ECS, 5×ECS, and 10×ECS. Repetitive ECS did not effect c-Jun and JunD expression. In a second model of systemic excitation of the brain, repetitive daily injection of kainic acid for 4 days completely failed to express c-Fos, c-Jun, and JunB after the last application whereas injection of kainic acid once per week did not alter the strong expressions compared to a single application of kainic acid. In order to study the maintenance of c-Fos expression during repetitive seizures, brain-derived neurotrophic factor (BDNF) was applied in parallel for 5 or 10 days via miniosmotic pumps and permanent cannula targeted at the hippocampus or the parietal cortex. Infusion of BDNF completely reinduced c-Fos expression during 5×ECS or 10×ECS in the cortex ipsilaterally to the cannula and, to a less extent, also increased the expression of c-Jun and JunB when compared to saline-treated controls. BDNF had no effect on the expression patterns in the hippocampus. ECS with or without BDNF infusion did not change the expression patterns of the constitutive transcription factors ATF-2, CREB, and SRF. These data demonstrate that various transcription factors substantially differ in their response to acute and chronic neural stimulation. Repetitive pathophysiological excitation decreases the transcriptional actions of neurons over days in the adult brain, and this decrement can be prevented by BDNF restoring the neuroplasticity at the level of gene transcription.

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      The dissected VMH and the residual brain sections from a typical microdissection are shown in Fig. 2. To confirm the gene expression changes induced by ECS in the dissected VMH samples, we examined the expression of the fos and jun families of immediate-early genes, which are induced rapidly but transiently in the brain in response to various stimuli, including ECS (Hsieh et al., 1998). A single ECS treatment robustly induced the expression of Fos (c-Fos; t(6) = 4.412, p < 0.01), Fosb (FosB; t(6) = 4.95, p < 0.01), and Jun (c-Jun; t(6) = 4.41, p < 0.01) in the VMH 2 h after stimulation (Fig. 3A–C).

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      It can also be transported to terminals [11], and upon release both stimulate and inhibit other hippocampal neurons [6]; e.g. by enhancing transmitter release [40], by enhancing AMPA- and GABA-mediated currents, and by inhibiting their responses to GABA [80], and by lasting phosphorylation of their trk [41,59] and NMDA receptors [79] which induces ITF expression. However, the mutual modulation of BDNF and c-Fos is not simple because, although infusion of BDNF into the hippocampus restores the expression of c-Fos after its down-regulation by repeated electroconvulsive seizures, BDNF alone appears not to induce c-Fos in the hippocampus [30]. Brief stimulation can cause persisting changes in the composition and functioning of AMPA and NMDA receptors [42], which again will affect ITF expressions.

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