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Long-term potentiation (LTP) at hippocampal CA3-CA1 synapses is thought to be mediated, at least in part, by an increase in the postsynaptic surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors induced by N-methyl-d-aspartate (NMDA) receptor activation. While this process was originally attributed to the regulated synaptic insertion of GluA1 (GluR-A) subunit-containing AMPA receptors, recent evidence suggests that regulated synaptic trafficking of GluA2 subunits might also contribute to one or several phases of potentiation. However, it has so far been difficult to separate these two mechanisms experimentally. Here we used genetically modified mice lacking the GluA1 subunit (Gria1(-/-) mice) to investigate GluA1-independent mechanisms of LTP at CA3-CA1 synapses in transverse hippocampal slices. An extracellular, paired theta-burst stimulation paradigm induced a robust GluA1-independent form of LTP lacking the early, rapidly decaying component characteristic of LTP in wild-type mice. This GluA1-independent form of LTP was attenuated by inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC), two enzymes known to regulate GluA2 surface expression. Furthermore, the induction of GluA1-independent potentiation required the activation of GluN2B (NR2B) subunit-containing NMDA receptors. Our findings support and extend the evidence that LTP at hippocampal CA3-CA1 synapses comprises a rapidly decaying, GluA1-dependent component and a more sustained, GluA1-independent component, induced and expressed via a separate mechanism involving GluN2B-containing NMDA receptors, neuronal nitric oxide synthase and PKC.

Original publication

DOI

10.1111/j.1460-9568.2009.06677.x

Type

Journal article

Journal

Eur J Neurosci

Publication Date

03/2009

Volume

29

Pages

1141 - 1152

Keywords

Analysis of Variance, Animals, Biophysics, Electric Stimulation, Enzyme Inhibitors, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Gene Expression, Hippocampus, In Vitro Techniques, Long-Term Potentiation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Net, Nitric Oxide Synthase Type I, Protein Kinase C, Receptors, AMPA