Essential regulatory functions of CaMKII T286 phosphorylation in LTP and two distinct forms of LTD

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) mediates both long-term potentiation and depression (LTP and LTD) of excitatory synapses, two opposing forms of synaptic plasticity induced by strong versus weak stimulation of NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD is prevalent in juvenile hippocampus, but in mature hippocampus, LTD is still readily induced by stimulating metabotropic glutamate receptors (mGluRs). Here we show that mGluR-dependent LTD also requires CaMKII and its T286 autophosphorylation that induces Ca2+-independent autonomous kinase activity. This autophosphorylation (i) accelerated CaMKII movement to excitatory synapses after LTP stimuli and (ii) was required for the movement to inhibitory synapses after NMDAR-LTD stimuli. Similar to NMDAR-LTD, the mGluR-LTD stimuli did not induce any CaMKII movement to excitatory synapses. However, in contrast to NMDAR-LTD, the mGluR-LTD did not involve CaMKII movement to inhibitory synapses and did not require additional T305/306 autophosphorylation. Taken together, even though CaMKII T286 autophosphorylation has a longstanding prominent role in LTP, it is also required for both major forms of LTD in hippocampal neurons, albeit with differential requirements for the heterosynaptic communication of excitatory signals to inhibitory synapses.

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(RS)-alpha-methyl-4-carboxyphenylglycine neither prevents induction of LTP nor antagonizes metabotropic glutamate receptors in CA1 hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1993.70.6.2684 ◽

1993 ◽

Vol 70 (6) ◽

pp. 2684-2689 ◽

Cited By ~ 81

Author(s):

P. Chinestra ◽

L. Aniksztejn ◽

D. Diabira ◽

Y. Ben-Ari

Keyword(s):

Glutamate Receptors ◽

Hippocampal Neurons ◽

Metabotropic Glutamate Receptors ◽

Regional Distribution ◽

Long Term Potentiation ◽

Excitatory Postsynaptic Potential ◽

Metabotropic Receptors ◽

Metabotropic Glutamate ◽

Term Potentiation ◽

Ca1 Pyramidal Neuron

1. The effects of the putative antagonist of metabotropic glutamate receptors (mGluR), (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), were investigated in CA1 hippocampal neurons using intracellular and extracellular recordings. 2. MCPG (0.5 mM) did not antagonize the characteristic block of the slow afterhyperpolarization and spike accomodation produced by the selective mGluR agonist, 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (30 microM). 3. MCPG (0.5 mM) did not prevent the inward current produced by 1S,3R-ACPD (30 microM) [240 +/- 14 and 255 +/- 21 pA (mean +/- SD) in the absence and in presence of MCPG, respectively]. 4. MCPG (0.5 mM, 10 min) did not prevent the presynaptically mediated reduction by 1S,3R-ACPD (50 microM, 10 min) of the field excitatory postsynaptic potential (EPSP) (51 +/- 7 and 64 +/- 10% in the absence and in presence of MCPG, respectively). 5. MCPG (0.5 mM) did not prevent the induction of long-term potentiation by a high-frequency tetanic stimulation of Schaffer collaterals (100 Hz, 1 s) (+61 +/- 5 and +67 +/- 16% increase in the absence and presence of MCPG, respectively). 6. These observations suggest that MCPG is not an antagonist of the subtypes of mGlu receptors that are present in CA1 pyramidal neuron. Possible selectivity of this compound for specific mGluRs is discussed in view of the regional distribution of metabotropic receptors in the hippocampus.

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Long-term potentiation by activation of group I metabotropic glutamate receptors at excitatory synapses in the spinal trigeminal subnucleus oralis

Neuroscience Letters ◽

10.1016/j.neulet.2013.11.056 ◽

2014 ◽

Vol 560 ◽

pp. 36-40 ◽

Cited By ~ 6

Author(s):

Dong-ho Youn

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Long Term Potentiation ◽

Excitatory Synapses ◽

Metabotropic Glutamate ◽

Group I ◽

Term Potentiation

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Activity-dependent regulation of synaptic strength by PSD-95 in CA1 neurons

Journal of Neurophysiology ◽

10.1152/jn.00526.2011 ◽

2012 ◽

Vol 107 (4) ◽

pp. 1058-1066 ◽

Cited By ~ 26

Author(s):

Peng Zhang ◽

John E. Lisman

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Synaptic Strength ◽

Ca1 Neurons ◽

Metabotropic Glutamate ◽

Group I ◽

Term Potentiation ◽

Activity Dependent

CaMKII and PSD-95 are the two most abundant postsynaptic proteins in the postsynaptic density (PSD). Overexpression of either can dramatically increase synaptic strength and saturate long-term potentiation (LTP). To do so, CaMKII must be activated, but the same is not true for PSD-95; expressing wild-type PSD-95 is sufficient. This raises the question of whether PSD-95's effects are simply an equilibrium process [increasing the number of AMPA receptor (AMPAR) slots] or whether activity is somehow involved. To examine this question, we blocked activity in cultured hippocampal slices with TTX and found that the effects of PSD-95 overexpression were greatly reduced. We next studied the type of receptors involved. The effects of PSD-95 were prevented by antagonists of group I metabotropic glutamate receptors (mGluRs) but not by antagonists of ionotropic glutamate receptors. The inhibition of PSD-95-induced strengthening was not simply a result of inhibition of PSD-95 synthesis. To understand the mechanisms involved, we tested the role of CaMKII. Overexpression of a CaMKII inhibitor, CN19, greatly reduced the effect of PSD-95. We conclude that PSD-95 cannot itself increase synaptic strength simply by increasing the number of AMPAR slots; rather, PSD-95's effects on synaptic strength require an activity-dependent process involving mGluR and CaMKII.

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