The progressive development of
seizures in rats by amygdala kindling, which models
temporal lobe epilepsy, allows the study of molecular regulators of enduring synaptic changes.
Neurotrophins play important roles in synaptic plasticity and neuroprotection.
Activin, a member of the
transforming growth factor-beta superfamily of growth and differentiation factors, has recently been added to the list of candidate synaptic regulators. We mapped the induction of
activin betaA mRNA in amygdala and cortex at several stages of seizure development. Strong induction, measured 2 hours after the first stage 2 (partial) seizure, appeared in neurons of the ipsilateral amygdala (confined to the lateral, basal, and posterior cortical nuclei) and insular, piriform, orbital, and infralimbic cortices.
Activin betaA mRNA induction, after the first stage 5 (
generalized) seizure, had spread to the contralateral amygdala (same nuclear distribution) and cortex, and the induced labeling covered much of the convexity of neocortex as well as piriform, perirhinal, and entorhinal cortices in a nearly bilaterally symmetrical pattern. This pattern had filled in by the sixth stage 5 seizure. Induced labeling in cortical neurons was confined mainly to layer II. A similar temporal and spatial pattern of increased
mRNA expression of
brain-derived neurotrophic factor (
BDNF) was found in the amygdala and cortex.
Activin betaA and
BDNF expression patterns were similar at 1, 2, and 6 hours after the last seizure, subsiding at 24 hours; in contrast, c-fos
mRNA induction appeared only at 1 hour throughout cortex and then subsided. In double-label studies,
activin betaA mRNA-positive neurons were also
BDNF mRNA positive, and they did not colocalize with GAD67
mRNA (a marker of gamma-aminobutyric acidergic neurons). The data suggest that
activin and
BDNF transcriptional activities accurately mark excitatory neurons participating in seizure-induced synaptic alterations and may contribute to the enduring changes that underlie the kindled state.