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The Journal of Neuroscience, March 28, 2007, 27(13):3523-3534; doi:10.1523/JNEUROSCI.4340-06.2007

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Cellular/Molecular
Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

Eric A. Horne¹ and Mark L. Dell'Acqua^1,2

¹Department of Pharmacology ²Program in Neuroscience, School of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045

Correspondence should be addressed to Mark L. Dell'Acqua, Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, 12800 East 19th Avenue, Mail Stop 8303, P.O. Box 6511, Aurora, CO 80045. Email: mark.dellacqua{at}uchsc.edu

NMDA receptor (NMDAR)-dependent hippocampal synaptic plasticity underlying learning and memory coordinately regulates dendritic spine structure and AMPA receptor (AMPAR) postsynaptic strength through poorly understood mechanisms. Induction of long-term depression (LTD) activates protein phosphatase 2B/calcineurin (CaN), leading to dendritic spine shrinkage through actin depolymerization and AMPAR depression through receptor dephosphorylation and internalization. The scaffold proteins A-kinase-anchoring protein 79/150 (AKAP79/150) and postsynaptic density 95 (PSD95) form a complex that controls the opposing actions of the cAMP-dependent protein kinase (PKA) and CaN in regulation of AMPAR phosphorylation. The AKAP79/150–PSD95 complex is disrupted in hippocampal neurons during LTD coincident with internalization of AMPARs, decreases in PSD95 levels, and loss of AKAP79/150 and PKA from spines. AKAP79/150 is targeted to spines through binding F-actin and the phospholipid phosphatidylinositol-(4,5)-bisphosphate (PIP₂). Previous electrophysiological studies have demonstrated that inhibition of phospholipase C (PLC)-catalyzed hydrolysis of PIP₂ inhibits NMDAR-dependent LTD; however, the signaling mechanisms that link PLC activation to alterations in dendritic spine structure and AMPAR function in LTD are unknown. We show here that NMDAR stimulation of PLC in cultured hippocampal neurons is necessary for AKAP79/150 loss from spines and depolymerization of spine actin. Importantly, we demonstrate that NMDAR activation of PLC is also necessary for decreases in spine PSD95 levels and AMPAR internalization. Thus, PLC signaling is required for structural and functional changes in spine actin, PSD scaffolding, and AMPAR trafficking underlying postsynaptic expression of LTD.

Key words: phospholipase C; LTD; actin; phosphatidylinositol-(4,5)-bisphosphate; A kinase-anchoring protein; PSD95; AMPA receptor

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Received Oct. 4, 2006; revised Feb. 22, 2007; accepted Feb. 23, 2007.

Correspondence should be addressed to Mark L. Dell'Acqua, Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, 12800 East 19th Avenue, Mail Stop 8303, P.O. Box 6511, Aurora, CO 80045. Email: mark.dellacqua{at}uchsc.edu

This article has been cited by other articles:

				X.-b. Wang, Y. Yang, and Q. Zhou Independent Expression of Synaptic and Morphological Plasticity Associated with Long-Term Depression J. Neurosci., November 7, 2007; 27(45): 12419 - 12429. [Abstract] [Full Text] [PDF]

				L. Gao Phosphatidylinositol-4,5-Bisphosphate and {alpha}-Actinin: Two-Component Hinge for the NMDA Receptor J. Neurosci., September 26, 2007; 27(39): 10321 - 10322. [Full Text] [PDF]

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