Proneurotrophins, seizures, and neuronal apoptosis

Abstract

Neurons respond to numerous factors in their environment that influence their survival and function during development and in the mature brain. Among these factors, the neurotrophins have been shown to support neuronal survival and function, acting primarily through the Trk family of receptor tyrosine kinases. However, recent studies have established that the uncleaved neurotrophin precursors, the proneurotrophins, can be secreted and induce apoptosis via the p75 neurotrophin receptor, suggesting that the balance of secreted mature and proneurotrophins has a critical impact on neuronal survival or death. Epileptic seizures elicit increases in both proneurotrophin secretion and p75(NTR) expression, shifting the balance of these factors toward signaling cell death. This review will discuss the evidence that this ligand-receptor system plays an important role in neuronal loss following seizures.

Figure 1

Schematic diagram showing the receptor interactions of mature and proneurotrophins.

Figure 2

p75 is required for neuronal death following pilocarpine-induced seizures. Sections through the hippocampus from wild-type (a) or p75−/− (b) mice were stained with fluorojade B to label dying neurons. In the p75−/− mice, there was an 80% reduction in the number of dying neurons in the hippocampus compared with wild type. Size bar = 100 μm. Reprinted with permission from Troy and others. 2002. J Biol Chem 277(37):34295–302.

Figure 3

Anti-proNGF prevents neuronal loss after seizures in vivo. Rats were cannulated bilaterally in the dorsal hippocampus 1 week prior to seizure. Following seizures anti-proNGF (1.5 μg/0.5 μL) was injected on one side and control rabbit IgG on the other side. Cleaved caspase-3 (a, b) and fluorojade B labeling (c, d) combined with immunostaining for p75^NTR (e-h) demonstrated a decrease in the number of dying neurons with the anti-proNGF relative to the control IgG in the same brains. Size bar in a = 100 μm and is the same for b; size bar in h represents 50 μm and is the same for c-g. Reprinted with permission from Volosin and others. 2008. J Neurosci 28(39):9870–9.

Figure 4

Schematic diagram showing the interaction of the p75^NTR and TrkB signaling pathways. Activation of p75^NTR blocks signaling from TrkB downstream of the receptor, allowing the apoptotic pathway to proceed.