The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning

Zhou, Zikai; Liu, An; Xia, Shuting; Leung, Celeste; Qi, Junxia; Meng, Yanghong; Xie, Wei; Park, Pojeong; Collingridge, Graham L.; Jia, Zhengping

doi:10.1038/s41593-017-0030-z

Cited by 116 publications

(113 citation statements)

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“…AMPAR subunits have multiple phosphorylation sites on their C-terminal tails, thought to regulate channel function[53] and especially plasticity[54]. GluA1 subunit phosphorylation at S831, S818 and T849 may play a role in regulating channel conductance[20, 21, 24, 55], while S845 may play a role in Po[44] and regulating receptor trafficking in the membrane[53].…”

Section: Multiple Factors Regulate Ampar Conductance In Hippocampusmentioning

confidence: 99%

AMPA-Type Glutamate Receptor Conductance Changes and Plasticity: Still a Lot of Noise

Benke

Traynelis

2018

Neurochem Res

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Twenty years ago, we reported from the Collingridge Lab that a single-channel conductance increase through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPARs) could mediate one form of plasticity associated with long-term potentiation (LTP) in the hippocampus (Benke et al., Nature 395:793-797, 1998). Revealed through peak-scaled non-stationary fluctuation analysis (PS-NSFA, also known as noise analysis), this component of LTP could be exclusively mediated by direct increases in channel conductance or by increases in the number of high conductance synaptic AMPARs. Re-evaluation of our original data in the light of the molecular details regarding AMPARs, conductance changes and plasticity suggests that insertion of high-conductance GluA1 homomers can account for our initial findings. Any potential cost associated with manufacture or trafficking of new receptors could be mitigated if pre-existing synaptic AMPARs also undergo a modest conductance change. The literature suggests that the presence of high conductance AMPARs and/or GluA1 homomers confers an unstable synaptic state, suggesting state transitions. An experimental paradigm is proposed to differentiate these possibilities. Validation of this state diagram could provide insight into development, disease pathogenesis and treatment.

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Section: Multiple Factors Regulate Ampar Conductance In Hippocampusmentioning

confidence: 99%

AMPA-Type Glutamate Receptor Conductance Changes and Plasticity: Still a Lot of Noise

Benke

Traynelis

2018

Neurochem Res

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“…Unlike the Kal7-C and GluN2B peptides, cells filled with Kal7-GluN2B (10 M) showed no differences in LTD compared to control cells at any time post-induction and expressed robust LTD following LFS. The differences in the test peptide blocking results for LTP and LTD suggest important differences in the fundamental underlying causes of these long term changes in plasticity (Zhou et al, 2018). Specifically, GluA1 (which ends …ATGL; a Class 1 PDZ motif, as are the peptides being tested here) is crucial for LTP, while GluA2 (which ends …SVKI, a Class 2 PDZ motif) is crucial for LTD (Zhou et al, 2018).…”

Section: Acute Disruption Of Kal7→glun2a/b→psd95 Interactions Also mentioning

confidence: 92%

Dissecting the Roles of Kalirin-7/PSD95/GluN2B Interactions in Different Forms of Synaptic Plasticity

Yeh

Yasko

Levine

et al. 2019

Preprint

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is a Rac1/RhoG GEF and multidomain scaffold localized to the postsynaptic density which plays an important role in synaptic plasticity. Behavioral and physiological phenotypes observed in the Kal7 knockout mouse are quite specific: genetics of breeding, growth, strength and coordination are normal; Kal7 knockout animals self-administer cocaine far more than normal mice, show exaggerated locomotor responses to cocaine, but lack changes in dendritic spine morphology seen in wildtype mice; Kal7 knockout mice have depressed surface expression of GluN2B receptor subunits and exhibit marked suppression of long-term potentiation and depression in hippocampus, cerebral cortex, and spinal cord; and Kal7 knockout mice have dramatically blunted perception of pain. To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we administered intracellular blocking peptides to acutely change Kal7 function at the synapse, to determine if plasticity deficits in Kal7 -/mice are the product of developmental processes since conception, or could be detected on a much shorter time scale. We found that specific disruption of the interactions of Kal7 with PSD-95 or GluN2B resulted in significant suppression of longterm potentiation and long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.

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“…GluA2CTP due to different synaptic delivery mechanisms of GluA1-and GluA2-containing AMPARs 11,12 . GluA1CTP does not affect basal AMPAR-mediated currents but abolishes activity-dependent synaptic potentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Regulation of the trafficking of postsynaptic AMPAR underlies activitydependent plasticity of synaptic strength [8][9][10] . Regulatory sites within the C-terminal region of GluA1 and GluA2 subunits are required for synaptic trafficking of AMPARs 8,11 . Expression of peptides corresponding to the GluA C-terminal peptides (GluA1CTP or GluA2CTP) impairs AMPAR trafficking, decreases excitatory synaptic transmission and disrupts experiencedependent synaptic plasticity [12][13][14] .…”

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confidence: 99%

Cell-autonomous regulation of structural and functional plasticity in inhibitory neurons by excitatory synaptic inputs

Shen

Zheng

et al. 2017

Preprint

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Functional circuit assembly is thought to require coordinated development of excitation and inhibition, but whether they are co-regulated cell-autonomously remains unclear. We investigated effects of decreased glutamatergic synaptic input on inhibitory synapses by expressing AMPAR subunit, GluA1 and GluA2, C-terminal peptides (GluA1CTP and GluA2CTP) in developing Xenopus tectal neurons. GluACTP decreased excitatory synaptic inputs and cell-autonomously decreased inhibitory synaptic inputs in excitatory and inhibitory neurons. Visually-evoked excitatory and inhibitory currents decreased proportionately, maintaining excitation/inhibition. GluACTP affected dendrite structure and visual experience-dependent structural plasticity differently in excitatory and inhibitory neurons. Deficits in excitatory and inhibitory synaptic transmission and experience-dependent plasticity manifested in altered visual receptive field properties. Both visual avoidance behavior and learning-induced behavioral plasticity were impaired, suggesting that maintaining excitation/inhibition alone is insufficient to preserve circuit function. We demonstrate that excitatory synaptic dysfunction in individual neurons cell-autonomously decreases inhibitory inputs and disrupts neuronal and circuit plasticity, information processing and learning.

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The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning

Cited by 116 publications

References 50 publications

AMPA-Type Glutamate Receptor Conductance Changes and Plasticity: Still a Lot of Noise

AMPA-Type Glutamate Receptor Conductance Changes and Plasticity: Still a Lot of Noise

Dissecting the Roles of Kalirin-7/PSD95/GluN2B Interactions in Different Forms of Synaptic Plasticity

Cell-autonomous regulation of structural and functional plasticity in inhibitory neurons by excitatory synaptic inputs

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