SYNAPTIC PLASTICITY Parallel Pre- and Postsynaptic Pathways to Puncta and Potentiation?

N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation (LTP) of synaptic efficacy appears to involve early microstructural changes in which pre- and postsynaptic proteins aggregate into clusters (or puncta). Wang et al. used a combination of pharmacological analysis, immunocytochemistry, and electrophysiology in dissociated cultures of rat hippocampal neurons to investigate the signaling pathways that mediate glutamate-dependent development of pre- and postsynaptic puncta and long-lasting glutamate-dependent enhancement of synaptic communication in cultured neurons (long-lasting potentiation) and found evidence implicating a nitric oxide (NO), guanosine 3',5'-monophosphate (cGMP), and cGMP-dependent protein kinase (cGK) pathway. Immunocytochemical analysis further revealed that cGK1 and VASP (vasodilator-stimulated phosphoprotein, which is a substrate for cGK that is involved in the regulation of the actin cytoskeleton) were localized at both pre- and postsynaptic sites and that glutamate stimulated an increase in VASP phosphorylation at the cGK site. Pharmacological analysis implicated actin in glutamate-dependent increases in miniature excitatory postsynaptic current (mEPSC) frequency, and experiments in which glutamate-dependent increases in EPSC amplitude in cultured neurons were measured implicated both pre- and postsynaptic actin in the response. Long-lasting potentiation of mEPSC frequency and glutamate-dependent increases in pre- and postsynaptic puncta involved Rho GTPases and Rho kinase (ROCK), and experiments measuring tetanic stimulation-dependent potentiation of the EPSC between individual neurons in culture indicated that both pre- and postsynaptic RhoA were involved. RhoA and ROCK appeared to act both in parallel with the NO-cGMP-cGK-VASP pathway in regulating actin, and also upstream of cGMP.

H.-G. Wang, F.-M. Lu, I. Jin, H. Udo, E. R. Kandel, J. de Vente, U. Walter, S. M. Lohmann, R. D. Hawkins, I. Antonova, Presynaptic and postsynaptic roles of NO, cGK, and RhoA in long-lasting potentiation of and aggregation of synaptic proteins. Neuron 45, 389-403 (2005). [PubMed]