The CaMKII/NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms
Open accessAbstract
CaMKII is one of the most studied synaptic proteins, but many critical issues regarding its role in synaptic function remain unresolved. Using a CRISPR-based system to delete CaMKII and replace it with mutated forms in single neurons, we have rigorously addressed its various synaptic roles. In brief, basal AMPAR and NMDAR synaptic transmission both require CaMKIIα, but not CaMKIIβ, indicating that, even in the adult, synaptic transmission is determined by the ongoing action of CaMKIIα. While AMPAR transmission requires kinase activity, NMDAR transmission does not, implying a scaffolding role for the CaMKII protein instead. LTP is abolished in the absence of CaMKIIα and/or CaMKIIβ and with an autophosphorylation impaired CaMKIIα (T286A). With the exception of NMDAR synaptic currents, all aspects of CaMKIIα signaling examined require binding to the NMDAR, emphasizing the essential role of this receptor as a master synaptic signaling hub.
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Both sLTP and LTP are greatly diminished in a CaMKII-dead mutant (K42K or K42M), despite its translocation.
“In support of these results, both sLTP (379) and LTP (121, 379) are greatly diminished in a CaMKII-dead mutant (K42K or K42M), despite its translocation.”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
The Discussion (page unavailable) says that substantial LTP remained with the CaMKIIα K42R mutation, contrary to the claim that LTP was greatly diminished in the kinase-dead mutant. The Results report loss of long-term sLTP with a different mutant, T286A; they do not establish the claimed sLTP result for K42K or K42M, or its translocation. (LLM, conf=0.85)
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Experimental — accuracy not yet measuredExpression of active CaMKII or direct delivery into the cell via the recording electrode has repeatedly revealed a roughly two- to threefold enhancement in the AMPAR EPSC but little change in the NMDAR EPSC.
“Expression of active CaMKII (121, 130–132, 209, 210, 212) or direct delivery into the cell via the recording electrode (199) has repeatedly revealed a roughly two- to threefold enhancement in the AMPAR EPSC but little change in the NMDAR EPSC (130–132).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
In Results, ‘CaMKII constitutive activity and the maintenance of LTP’ (Fig. 10; page unavailable), expression of constitutively active CaMKIIα increased AMPAR EPSCs to about 250% of control. The cited passages do not report NMDAR EPSCs for that active-kinase experiment, so they do not establish the claimed little change in NMDAR EPSCs. Direct delivery through a recording electrode is attributed to a different citation in the citing sentence. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMutations in the GluN2B CTD that cannot bind CaMKII, or competing constructs, produce highly variable effects on LTP, ranging from complete block to no block.
“The second approach utilizes mutations in the CTD of GluN2B that cannot bind CaMKII as replacement for the wt (CaMKII L1298A/R1300Q) (120, 121, 230) or either competing with overexpressed full-length constructs (GluN2B R1300S/Q1303D) (231) or competing by expressing just the wt GluN2B CTD (839–1482) (232). The results are highly variable as reviewed in Ref. 233, ranging from complete block of LTP”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
In Results (‘The synaptic actions of CaMKII require binding to NMDARs’; page unavailable), the paper describes replacing GluN2B with a mutant that cannot bind CaMKII. It measures basal synaptic transmission in that replacement experiment, not LTP. The Discussion reports that earlier GluN2B-binding mutations impaired LTP, but does not establish the claimed range from complete block to no block. (LLM, conf=0.85)
Experimental — accuracy not yet measuredExpressing constitutively active CaMKII on the background of GluN2B(L1298A-R1300Q) fails to enhance synaptic transmission.
“Furthermore, expressing a constitutively active CaMKII on the background of GluN2B(L1298A-R1300Q) failed to enhance synaptic transmission (121).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
In Results (‘The synaptic actions of CaMKII require binding to NMDARs’; Fig. 9), a CaMKII-binding-deficient GluN2B mutant prevented the synaptic enhancement produced by CaMKIIα T305A/T306A. But the paper identifies the constitutively active construct as T286D-T305A/T306A and reports its failed enhancement with a CaMKIIα I205K mutation instead (Results, ‘CaMKII constitutive activity and the maintenance of LTP’; Fig. 10). Our copy therefore does not establish the claimed combination of constitutively active CaMKII and GluN2B(L1298A-R1300Q). (LLM, conf=0.88)
Experimental — accuracy not yet measuredExpressing CA CaMKII fails to enhance AMPAR responses in cells with GluN2B(L1298A-R1300Q).
“expressing CA CaMKII failed to enhance AMPAR responses.”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
In Results (‘The synaptic actions of CaMKII require binding to NMDARs’; page unavailable), a GluN2B mutant prevented enhancement by CaMKIIα T305A/T306A, but the paper does not identify that construct as constitutively active CaMKII. Results (‘CaMKII constitutive activity and the maintenance of LTP’) and the Discussion report that constitutively active CaMKII failed to enhance responses when CaMKII itself carried the I205K mutation. The claimed outcome is supported, but not for the stated combination of constructs. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Replacement with GluN2B(L1298A-R1300Q) reduces AMPAR responses by approximately 50%, similar to the reduction seen by deleting CaMKII.
“Intriguingly, AMPAR responses were reduced ∼50%, similar to the reduction seen by deleting CaMKII”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
The Results (Fig. 9 caption; page not provided) report that replacement with GluN2Bmut left AMPAR responses at 48.5% of control. The Results and Discussion also report an approximately 50% reduction after CaMKIIα deletion. Our copy does not identify GluN2Bmut as L1298A-R1300Q, so that specific mutation designation remains unverified. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCa2+/CaM peeling away the autoinhibitory segment results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state.
“The first step involves Ca2+/CaM peeling away the autoinhibitory segment from the kinase domain. This results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state (64, 78, 119–121, 221).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
The Introduction (page not available) says Ca2+/CaM relieves CaMKII autoinhibition and that T286 autophosphorylation produces kinase activity that persists after Ca2+/CaM is removed. The Discussion identifies GluN2B as a CaMKII binding partner, but the paper does not establish that binding occurs without prior autophosphorylation or that the binding itself maintains CaMKII in an active state. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBinding of CaMKII to GluN2B is critical for the synaptic enhancement caused by CaMKII.
“This binding of CaMKII to GluN2B is critical for the synaptic enhancement caused by CaMKII (see sect. 6) (119–122).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
Deletion of CaMKIIβ impairs LTP, as does deletion of CaMKIIα.
“Interestingly, deletion of CaMKIIβ impairs LTP (121, 172, 175), as does the deletion of CaMKIIα.”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
Expression of CaMKIIα in cells lacking both isoforms fully rescues LTP.
“expression of CaMKIIα in cells lacking both isoforms fully rescues LTP (121).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
Expression of CaMKIIβ in cells lacking both CaMKIIα and CaMKIIβ fails to rescue LTP.
“expression of CaMKIIβ in cells lacking both CaMKIIα and CaMKIIβ fails to rescue LTP (121)”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
The results with genetic deletion of CaMKIIα are variable, some showing roughly a 50% block and some showing a complete block.
“the results with the genetic deletion of CaMKIIα are more variable, some showing roughly a 50% block (87, 204–206) but some showing a complete block (121, 207, 208).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
Cells in which CaMKII has been replaced with CaMKII containing the I205K mutation fail to express LTP.
“G: cells in which CaMKII has been replaced with CaMKII containing the I205K mutation fail to express LTP.”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
CA CaMKII containing the I205K mutation fails to potentiate synapses.
“E: CA CaMKII containing the I205K mutation (n = 15 pairs) fails to potentiate synapses.”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
Constitutively active CaMKII (T286D-T305A/T306A) in APV potentiates synapses.
“D: constitutively active CaMKII (T286D-T305A/T306A) (CA CaMKII) in 2-amino-5-phosphonopentanoic acid (APV) (n = 8 pairs) potentiates synapses.”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
LTP is entirely blocked when CaMKII has the I205K mutation.
“Not unexpectedly, LTP was entirely blocked, suggesting that the CaMKII-GluN2B complex is necessary for LTP (FIGURE 6G).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
CA CaMKII containing the I205K mutation fails to enhance synaptic responses.
“the CA CaMKII containing the I205K mutation failed to enhance responses (FIGURE 6, E AND F).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
Replacement of wild-type GluN2B with GluN2B(L1298A-R1300Q) has no effect on NMDAR synaptic currents, indicating that the mutant is functional.
“Replacement with the mutant GluN2B had no effect on NMDAR synaptic currents, indicating that it is functional.”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
Constitutively active CaMKII (T286D-T305A/T306A) produces a typical approximately 2.5-fold enhancement of synaptic responses.
“Whereas CA CaMKII had its typical ∼2.5-fold enhancement (FIGURE 6, D AND F)”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
The CaMKII-GluN2B complex is necessary for LTP.
“Not unexpectedly, LTP was entirely blocked, suggesting that the CaMKII-GluN2B complex is necessary for LTP (FIGURE 6G).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
NMDAR-dependent LTP is greatly impaired when T286 is replaced by T286A.
“Foremost are data, now long accepted, that NMDAR-dependent LTP is greatly impaired when T286 is replaced by T286A (43, 121, 381–384).”
From Synaptic memory and CaMKII (2023) · cites this paper as [121]
CaMKII is vital in controlling NMDA receptor activity, which also acts as a calcium channel.
“CaMKII is vital in controlling NMDA receptor activity (Incontro et al., 2018), which also acts as a calcium channel (Lau et al., 2009).”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Incontro et al., 2018
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References 81 · Cited by 171
- Authors
- Incontro, S., Díaz-Alonso, J., Iafrati, J., Vieira, M., Asensio, C. S., Sohal, V. S., Roche, K. W., Bender, K. J., & Nicoll, R. A.
- Affiliations
- University of California, San Francisco (US)
- National Institutes of Health (US)
- Corresponding author
- Incontro, Salvatore
- Nicoll, Roger A.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-05-25
- Volume
- 9
- Issue
- 1
- Pages
- 2069-2069
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5970233
- OpenAlex
- W2804368056
- Cited by
- 171
- References
- 81
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 24 · 2023: 25 · 2022: 28 · 2021: 21 · 2020: 22 · 2019: 14 · 2018: 6
- FWCI
- 7.18
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-12-03)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- University of California, San Francisco
- Fundação para a Ciência e a Tecnologia
- National Institute of Mental Health (R01MH070957, R01MH100292, R01MH117139)
- National Institute on Drug Abuse (R01DA035913)
- National Institute of General Medical Sciences (R15GM116096, R01GM124035)
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CaMKII, NMDA receptor, AMPA receptors, hippocampal synaptic transmission, CaMKIIα, CaMKIIβ, long-term potentiation, autophosphorylation
- MeSH terms
- Animals, Cell Membrane, Female, Hippocampus, Humans, Synaptic Transmission, Neurons, Phosphorylation, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Receptors, Glutamate, Long-Term Potentiation, Mice, Knockout, Mice, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, HEK293 Cells, CRISPR-Cas Systems
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