Postsynaptic Calcineurin Activity Downregulates Synaptic Transmission by Weakening Intracellular Ca<sup>2+</sup>Signaling Mechanisms in Hippocampal CA1 Neurons

Wang, Jinhui; Kelly, Paul

doi:10.1523/jneurosci.17-12-04600.1997

Cited by 110 publications

(48 citation statements)

References 75 publications

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“…Prior studies have reported complex effects of FK506 on LTP-including developmental differences. In hippocampal slices from adult animals, FK506 caused LTP induction, whereas in hippocampal slices from young animals, FK506 prevented LTP induction (Wang and Kelly 1997;Wang and Stelzer 1994). However, in other studies using hippocampal slices from young animals, LTP induction was not prevented in FK506-treated slices (Mulkey et al 1994).…”

Section: Effect Of Calcineurin Inhibition On Tb Depotentiationmentioning

confidence: 77%

Protein Phosphatases Mediate Depotentiation Induced by High-Intensity Theta-Burst Stimulation

Kang-Park¹,

Sarda²,

Jones³

et al. 2003

Journal of Neurophysiology

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Wilson. Protein phosphatases mediate depotentiation induced by highintensity theta-burst stimulation. J Neurophysiol 89: 684 -690, 2003; 10.1152/jn.01041.2001. We have previously reported that varying stimulus intensity produces qualitatively different types of synaptic plasticity in area CA1 of hippocampal slices: brief low-intensity (LI) theta-burst (TB) stimuli induce long-term potentiation (LTP), but if the stimulus intensity is increased (to mimic conditions that may exist during seizures), LTP is not induced; instead, high-intensity (HI) TB stimuli erase previously induced LTP ("TB depotentiation"). We now have explored the mechanisms underlying TB depotentiation using extracellular field recordings with pharmacological manipulations. We found that TB depotentiation was blocked by okadaic acid and calyculin A (inhibitors of serine/threonine protein phosphatases PP1 and PP2A), FK506 (a specific blocker of calcineurin, a Ca 2ϩ /calmodulin (CaM) protein phosphatase), and 8-Br-cAMP (an activator of protein kinase A) with 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). These results suggest that protein phosphatase pathways are involved in the TB depotentiation similar to other type of down-regulating synaptic plasticity such as low-frequency stimulation (LFS)-induced long-term depression (LTD) and depotentiation in the rat hippocampus. However, TB depotentiation and LFS depotentiation could have differential functional significance.

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Section: Effect Of Calcineurin Inhibition On Tb Depotentiationmentioning

confidence: 77%

Protein Phosphatases Mediate Depotentiation Induced by High-Intensity Theta-Burst Stimulation

Kang-Park¹,

Sarda²,

Jones³

et al. 2003

Journal of Neurophysiology

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“…Calcineurin, which is activated by Ca 2ϩ and calmodulin, is colocalized with PKA at A kinase anchor proteins (AKAPs) in neurites (Coghlan et al, 1995;Fraser and Scott, 1999), suggesting that these two enzymes are well positioned to exert opposing actions on their substrates. Potentiation of postsynaptic responses by inhibition of postsynaptic calcineurin appears to occlude induction of LTP (Wang and Stelzer, 1994;Wang and Kelly, 1997); calcineurin has also been suggested to play a role in LTD (Mulkey et al, 1994).…”

Section: Abstract: Ampa Receptors; Glutamate; Ltd; Pka; Calcineurin;mentioning

confidence: 99%

Control of GluR1 AMPA Receptor Function by cAMP-Dependent Protein Kinase

et al. 2000

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Modulation of postsynaptic AMPA receptors in the brain by phosphorylation may play a role in the expression of synaptic plasticity at central excitatory synapses. It is known from biochemical studies that GluR1 AMPA receptor subunits can be phosphorylated within their C terminal by cAMP-dependent protein kinase A (PKA), which is colocalized with the phosphatase calcineurin (i.e., phosphatase 2B). We have examined the effect of PKA and calcineurin on the time course, peak open probability (P O,PEAK ), and single-channel properties of glutamateevoked responses for neuronal AMPA receptors and homomeric GluR1(flip) receptors recorded in outside-out patches. Inclusion of purified catalytic subunit C␣-PKA in the pipette solution increased neuronal AMPA receptor P O,PEAK (0.92) compared with recordings made with calcineurin included in the pipette (P O,PEAK 0.39). Similarly, C␣-PKA increased P O,PEAK for recombinant GluR1 receptors (0.78) compared with patches excised from cells cotransfected with a cDNA encoding the PKA peptide inhibitor PKI (P O,PEAK 0.50) or patches with calcineurin included in the pipette (P O,PEAK 0.42). Neither PKA nor calcineurin altered the amplitude of single-channel subconductance levels, weighted mean unitary current, mean channel open period, burst length, or macroscopic response waveform for recombinant GluR1 receptors. Substitution of an amino acid at the PKA phosphorylation site (S845A) on GluR1 eliminated the PKA-induced increase in P O,PEAK , whereas the mutation of a Ca 2ϩ ,calmodulin-dependent kinase II and PKC phosphorylation site (S831A) was without effect. These results suggest that AMPA receptor peak response open probability can be increased by PKA through phosphorylation of GluR1 Ser845. Key words: AMPA receptors; glutamate; LTD; PKA; calcineurin; open probability; GluR1Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory neurotransmission in the mammalian CNS. These glutamate receptors can be subdivided on the basis of agonist pharmacology and sequence homology into three classes, which include N-methyl-D-aspartate, kainate, and AM PA receptors. AM PA receptors mediate fast synaptic current at most excitatory synapses and are tetrameric or pentameric complexes assembled from any of four different subunits (GluR1-4) with variable stoichiometry (Hollmann and Heinemann, 1994;Dingledine et al., 1999).The modulation of excitatory synaptic transmission during long-term potentiation (LTP) and long-term depression (LTD), two well established cellular models of learning and memory, results from changes in the presynaptic release of glutamate and/or changes in postsynaptic glutamate receptor f unction or localization (

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“…The inactivation of CaN facilitates protein phosphorylation (Wang and Kelly, 1997), which might lead to the conversion of synaptic patterns. To test this possibility, we infused Ca 2+ -CaM (40/10 μM) into postsynaptic neurons, which activates protein kinases (Wang and Kelly, 1995) 159.97±7.21 pA over 0-4 minutes and 258.99±4.52 pA 50 minutes after the infusion (P=0.0001; green symbols in Fig.…”

Section: =07)mentioning

confidence: 99%

Gain and fidelity of transmission patterns at cortical excitatory unitary synapses improve spike encoding

Wang

Wei

Chen

et al. 2008

Journal of Cell Science

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Neuronal spike encoding and synaptic transmission in the brain need be precise and reliable for well-organized behavior and cognition. Little is known about how a unitary synapse reliably transmits presynaptic sequential spikes and how multiple unitary synapses precisely drive their postsynaptic neurons to encode spikes. To address these questions, we investigated the dynamics of glutamatergic unitary synapses as well as their role in driving the encoding of cortical fast-spiking neurons. Synaptic transmission patterns randomly fluctuate among facilitation, depression and parallel over time. The postsynaptic calmodulin-signaling pathway enhances initial responses and converts this fluctuation to a synaptic depression. We integrated current pulses mathematically based on synaptic plasticity and found that they improve spike capacity and timing precision by shortening the spike refractory period at postsynaptic neurons. Our results indicate that the gain and fidelity of synaptic patterns enable reliable transmission of presynaptic signals by the synapse and precise encoding of spikes by postsynaptic neurons. These reproducible neural codes may be involved in controlling well-organized behavior.

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Postsynaptic Calcineurin Activity Downregulates Synaptic Transmission by Weakening Intracellular Ca²⁺Signaling Mechanisms in Hippocampal CA1 Neurons

Cited by 110 publications

References 75 publications

Protein Phosphatases Mediate Depotentiation Induced by High-Intensity Theta-Burst Stimulation

Protein Phosphatases Mediate Depotentiation Induced by High-Intensity Theta-Burst Stimulation

Control of GluR1 AMPA Receptor Function by cAMP-Dependent Protein Kinase

Gain and fidelity of transmission patterns at cortical excitatory unitary synapses improve spike encoding

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Postsynaptic Calcineurin Activity Downregulates Synaptic Transmission by Weakening Intracellular Ca2+Signaling Mechanisms in Hippocampal CA1 Neurons

Cited by 110 publications

References 75 publications

Protein Phosphatases Mediate Depotentiation Induced by High-Intensity Theta-Burst Stimulation

Protein Phosphatases Mediate Depotentiation Induced by High-Intensity Theta-Burst Stimulation

Control of GluR1 AMPA Receptor Function by cAMP-Dependent Protein Kinase

Gain and fidelity of transmission patterns at cortical excitatory unitary synapses improve spike encoding

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Product

Resources

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Postsynaptic Calcineurin Activity Downregulates Synaptic Transmission by Weakening Intracellular Ca²⁺Signaling Mechanisms in Hippocampal CA1 Neurons