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The Journal of Neuroscience, February 16, 2005, 25(7):1654-1663; doi:10.1523/JNEUROSCI.3074-04.2005

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Cellular/Molecular
A Novel Pathway for Presynaptic Mitogen-Activated Kinase Activation via AMPA Receptors

Ursula Schenk,¹ Elisabetta Menna,¹ Taeyong Kim,² Maria Passafaro,^1,4 Sunghoe Chang,² Pietro De Camilli,³ and Michela Matteoli¹

¹Department of Medical Pharmacology, Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Center of Excellence on Neurodegenerative Diseases, University of Milan, 20129 Milan, Italy, ²Department of Life Science, Gwangju Institute of Science and Technology, Buk-gu, Gwangju 500-712, South Korea, ³Howard Hughes Medical Institute and Department of Cell Biology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06515, and ⁴Dulbecco Telethon Institute, 20129 Milan, Italy

AMPA-type glutamate receptors play a key role in mediating postsynaptic responses of excitatory neurotransmitters. It is now well accepted that AMPA receptors are also present at the presynapse, where they are thought to modulate neurotransmitter release. However, the mechanisms through which they control synaptic vesicle traffic have remained elusive. We used cultured hippocampal neurons and growth cone particles prepared from fetal rat brain to investigate the functional role of presynaptic AMPA receptors. We show here that stimulation of presynaptic AMPA receptors induces activation of mitogen-activated protein kinase (MAPK) through a nonreceptor tyrosine kinase-dependent and Na⁺/Ca²⁺-independent mechanism. This pathway is activated predominantly in axonal growth cones compared with the somatodendritic compartment. After stimulation of presynaptic AMPA receptors, synapsin I is phosphorylated at MAPK-specific sites. These events are paralleled by a prominent increase in evoked synaptic vesicle recycling that is blocked by the specific MAPK inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one. Similarly, in synaptosomes isolated from adult brain, AMPA stimulation induces MAPK activation and phosphorylation of synapsin I at MAPK-dependent sites and enhances significantly synaptic vesicle recycling. These results reveal a novel pathway for activation of presynaptic MAPK and suggest a role of this pathway in the regulation of short-term presynaptic plasticity.

Key words: presynaptic AMPA receptor; MAP kinase; synaptic plasticity; vesicle recycling; growth cone; synaptogenesis

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Received July 28, 2004; revised November 29, 2004; accepted December 23, 2004.

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