The neuropeptide PACAP38 induces dendritic spine remodeling through ADAM10-N-cadherin signaling pathway.
The neuropeptide pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been implicated in the induction of synaptic plasticity at the excitatory glutamatergic synapse. In particular, recent studies have shown that it is involved in the regulation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Here we demonstrate the effect of PACAP38 on the modulation of dendritic spine morphology through a disintegrin and metalloproteinase 10 (ADAM10)-N-cadherin-AMPA receptor signaling pathway. Treatment of primary hippocampal neurons with PACAP38 induced an accumulation of ADAM10 at the postsynaptic membrane. This event led to a significant decrease of dendritic spine head width and to a concomitant reduction of GluR1 colocalization with postsynaptic markers. The PACAP38-induced effect on dendritic spine head width was prevented by either treatment with the ADAM10-specific inhibitor or transfection of a cleavage-defective N-cadherin construct mutated in the ADAM10 cleavage site. Overall, our findings reveal that PACAP38 is involved in the modulation of dendritic spine morphology in hippocampal neurons, and assign to the ADAM10-N-cadherin signaling pathway a crucial role in this modification of the excitatory glutamatergic synapse.
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. fabrizio.gardoni@unimi.it
Fabrizio
F
Gardoni
Claudia
C
Saraceno
Matteo
M
Malinverno
Elena
E
Marcello
Chiara
C
Verpelli
Carlo
C
Sala
Monica
M
Di Luca
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072197:ADAM10 Protein; D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D049229:Dendritic Spines / Q000378:metabolism*; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000502:physiology*; D061251:Primary Cell Culture; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
D015820:Cadherins; C570099:N-cadherin, rat; D009419:Nerve Tissue Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018698:Glutamic Acid; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C542371:ADAM10 protein, rat