Serotonin-induced regulation of the actin network for learning-related synaptic growth requires Cdc42, N-WASP, and PAK in Aplysia sensory neurons.
Application of Clostridium difficile toxin B, an inhibitor of the Rho family of GTPases, at the Aplysia sensory to motor neuron synapse blocks long-term facilitation and the associated growth of new sensory neuron varicosities induced by repeated pulses of serotonin (5-HT). We have isolated cDNAs encoding Aplysia Rho, Rac, and Cdc42 and found that Rho and Rac had no effect but that overexpression in sensory neurons of a dominant-negative mutant of ApCdc42 or the CRIB domains of its downstream effectors PAK and N-WASP selectively reduces the long-term changes in synaptic strength and structure. FRET analysis indicates that 5-HT activates ApCdc42 in a subset of varicosities contacting the postsynaptic motor neuron and that this activation is dependent on the PI3K and PLC signaling pathways. The 5-HT-induced activation of ApCdc42 initiates reorganization of the presynaptic actin network leading to the outgrowth of filopodia, some of which are morphological precursors for the learning-related formation of new sensory neuron varicosities.
Udo
Hiroshi
H
Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Jin
Iksung
I
Kim
Joung-Hun
JH
Li
Hsiu-Ling
HL
Youn
Trisha
T
Hawkins
Robert D
RD
Kandel
Eric R
ER
Bailey
Craig H
CH
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001048:Aplysia; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000235:genetics; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000302:isolation & purification; D017434:Protein Structure, Tertiary / Q000235:genetics; D011554:Pseudopodia / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism
D000199:Actins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D012701:Serotonin; D010738:Type C Phospholipases; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins