Induction of beta-A activin expression by synaptic activity and during neocortical development

Abstract

beta-A activin is a member of the transforming growth factor-beta family and has been implicated in nerve cell survival and inhibition of differentiation in vitro [Hashimoto M. et al. (1990) Biochem. biophys. Res. Commun. 173, 193-200; Schubert D. et al. (1990) Nature 344, 868-870]. In our studies to identify genomic mechanisms involved in long-term neuronal responses to synaptic activity, we have determined that beta-A activin messenger RNA is rapidly and transiently induced in neurons of the adult rat brain by excitatory synaptic input. Synaptic mechanisms involved in beta-A activin messenger RNA induction were examined in adult hippocampus and cortex using the long-term potentiation paradigm. beta-A activin messenger RNA is induced in granule cell neurons of the hippocampus by high-frequency synaptic stimuli that produce long-term potentiation, and this induction is blocked by the N-methyl-D-aspartate type glutamate receptor antagonist, dizocilpine. beta-A activin messenger RNA is expressed at basal levels in neurons of layers II/III and V/VI, and this expression rapidly decreases following sensory deafferentation of the visual cortex or systemic administration of dizocilpine, suggesting that beta-A activin expression is regulated by physiological excitatory synaptic activity. In developing brain, beta-A activin is expressed in the neocortex and neostriatum beginning at embryonic day 17. beta-A activin expression in late fetal cortex is enriched in postmitotic neurons at the lower boundary of the dense cortical plate. As development progresses, beta-A activin expression continues to be enriched in neurons at the boundary between the hypercellular cortical plate and the subjacent, more mature deep layers. This inside-out progression of beta-A activin expression follows the well-characterized radial gradient of cortical development. Expression of beta-A activin messenger RNA is rapidly regulated in early postnatal cortex and striatum by GABA and glutamate antagonists, suggesting that beta-A activin is also regulated as a rapid response gene in developing brain, and that the high basal levels reflect a steady-state response to developmental signals. Since activin receptors are enriched in neurons of developing and adult brain [Cameron V. A. et al. (1994) Endocrinology 134, 799-808; Roberts V. J. and Barth S. L. (1994) Endocrinology 134, 914-922], our observations suggest a role for activin signaling in neuronal responses to synaptic and developmental activity. In this study, we analyse the induction of expression of beta-A activin, a member of the transforming growth factor-beta family of secreted peptides, in response to synaptic activity and in the developing brain. The elevated and specific expression of beta-A activin during fetal and early postnatal neocortical development and its later regulation by excitatory activity postnatally and in the adult suggests that the activin signaling pathway functions at multiple developmental stages in the neuroplastic response.