Figure 1.

Signaling pathways acutely activated in hippocampal neurons following seizures. Pathways downstream of glutamate, serotonin and dopamine receptors are illustrated. Seizures induce massive influx of Ca²⁺ through NMDA receptors and voltage-gated Ca²⁺ channels (in green), leading to CREB phosphorylation via ERK and calmodulin-dependent signaling, respectively (West et al., 2002). Serotonin and dopamine signaling modulate seizure-induced CREB phosphorylation via the activation of DARPP-32 and ERK1/2. Once phosphorylated, CREB promotes the transcription of activity-dependent genes such as BDNF and the IEGs fos and jun. The sustained induction of jun has been shown to switch on apoptotic cascades, whereas the pro-apoptotic role of fos induction has been questioned. Dendritic localization of BDNF mRNA and protein may also contribute to long-term excitability. The proposed scheme is a general (though not complete) summary of the intracellular pathways induced by seizures in the hippocampus. All the reported serotonin and dopamine receptor subtypes are expressed in the hippocampus, together with their signaling proteins (Meador-Woodruff et al., 1991; Perez and Lewis, 1992; Hannon and Hoyer, 2008). However, important differences may occur in different types of hippocampal neurons (e.g., dentate granule cells, pyramidal neurons), due to the different expression levels of these proteins. Abbreviations: AC, adenylate cyclase; CaM, calmodulin; CK1, casein kinase 1; DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32 kDa; D1R and D2R, dopamine receptors (D1 and D2 subtypes); ERK, extracellular-regulated kinase; GSK-3β, glycogen synthase kinase 3β; IEGs, immediate early genes; JNK, Jun-terminal kinase; NMDA, NMDA glutamate receptors; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PP-1, protein phosphatase 1; 5-HT, serotonin receptors. Question marks indicate that some pathways have been proposed but not clearly demonstrated.