ERK activation in axonal varicosities modulates presynaptic plasticity in the CA3 region of the hippocampus through synapsin I

Abstract

Activity-dependent changes in the strength of synaptic connections in the hippocampus are central for cognitive processes such as learning and memory storage. In this study, we reveal an activity-dependent presynaptic mechanism that is related to the modulation of synaptic plasticity. In acute mouse hippocampal slices, high-frequency stimulation (HFS) of the mossy fiber (MF)-CA3 pathway induced a strong and transient activation of extracellular-regulated kinase (ERK) in MF giant presynaptic terminals. Remarkably, pharmacological blockade of ERK disclosed a negative role of this kinase in the regulation of a presynaptic form of plasticity at MF-CA3 contacts. This ERK-mediated inhibition of post-tetanic enhancement (PTE) of MF-CA3 synapses was both frequency-and pathway-specific and was observed only with HFS at 50 Hz. Importantly, blockade of ERK was virtually ineffective on PTE of MF-CA3 synapses in mice lacking synapsin I, 1 of the major presynaptic ERK substrates, and triple knockout mice lacking all synapsin isoforms displayed PTE kinetics resembling that of wildtype mice under ERK inhibition. These findings reveal a form of short-term synaptic plasticity that depends on ERK and is finely tuned by the firing frequency of presynaptic neurons. Our results also demonstrate that presynaptic activation of the ERK signaling pathway plays part in the activity-dependent modulation of synaptic vesicle mobilization and transmitter release.MAP kinase ͉ mossy fibers ͉ post-tetanic potentiation T he extracellular-regulated kinase (ERK) signaling pathway plays a crucial role in the regulation of activity-dependent changes in the strength of synaptic transmission in the hippocampus (1, 2). Indeed, multiple studies have shown that altering the normal function of ERK causes severe impairments of both short-and long-term forms of synaptic plasticity at hippocampal synapses (3-6, but see also ref. 7). Remarkably, behavioral analyses of animals with altered ERK signaling have revealed a crucial involvement of this cascade in learning and memory (8-10), supporting the idea that ERK-dependent synaptic plasticity is essential for cognitive processes.Because potential molecular substrates of ERK are present in distinct neuronal compartments (2), the precise subcellular location in which ERK activation occurs is a major determinant of ERK function. For example, phosphorylated ERK translocates into the nucleus and regulates gene expression in response to synaptic activity by directly or indirectly phosphorylating transcription factors (2,11,12). Moreover, there is increasing evidence that ERK phosphorylates target proteins in both dendritic (13-15) and axonal compartments (16,17). Synapsin I (Syn I), a synaptic vesicleassociated phosphoprotein implicated in the regulation of synaptic strength, is a major ERK substrate in nerve terminals and presents 3 ERK-dependent phosphorylation sites (18,19). Interestingly, it has been shown that ERK phosphorylation regulates the interaction of Syn I with the actin cytoskeleton, a mechanism that is...

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