Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures

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-β superfamily of growth and differentiation factors, has recently been added to the list of candidate synaptic regulators. We mapped the induction of activin βA 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 βA 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 βA 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 βA mRNA-positive neurons were also BDNF mRNA positive, and they did not colocalize with GAD67 mRNA (a marker of γ-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.