scholarly journals NMDA receptor-targeted enrichment of CaMKIIα improves fear memory

2021 ◽  
Author(s):  
Anthony Chifor ◽  
Jeongyoon Choi ◽  
Joongkyu Park
Keyword(s):  
Long Term Potentiation ◽  
Fear Memory ◽  
Phage Display Library ◽  
Calcium Calmodulin Dependent ◽  
Novel Approach ◽  
Term Potentiation ◽  
Mouse Hippocampus ◽  
Dependent Protein ◽  
A Subunit ◽  
Library Selection

Calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) is an essential player in long-term potentiation and memory formation. However, the establishment of effective molecular interventions with CaMKIIα to improve memory remains a long-standing challenge. Here we report a novel intrabody targeting GluN1, a subunit of N-methyl-D-aspartate receptors (NMDARs). We identify this anti-GluN1 intrabody (termed VHH Anti-GluN1; VHHAN1) by a synthetic phage display library selection and yeast-two-hybrid screenings. We validate specific targeting of VHHAN1 to GluN1 in heterologous cells and the mouse hippocampus. We further show that adeno-associated virus (AAV)-mediated expression of CaMKIIα fused with VHHAN1 is locally enriched at excitatory postsynaptic regions of the mouse hippocampus. We also find that the AAV- and VHHAN1-mediated postsynaptic enrichment of CaMKIIα in the hippocampus improves contextual fear memory in mice. This novel approach opens a new avenue to enhance memory ability in health and diseases.

AMPA receptor phosphorylation during synaptic plasticity

2005 ◽  
Vol 33 (6) ◽  
pp. 1354-1356 ◽  
Author(s):  
J. Boehm ◽  
R. Malinow
Keyword(s):  
Protein Kinase ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Dependent Protein Kinase ◽  
Enhanced Transmission ◽  
Calcium Calmodulin Dependent ◽  
Term Potentiation ◽  
Dependent Protein ◽  
Biochemical Analyses

A widely studied example of vertebrate plasticity is LTP (long-term potentiation), the persistent synaptic enhancement that follows a brief period of coinciding pre- and post-synaptic activity. During LTP, different kinases, including CaMKII (calcium/calmodulin-dependent protein kinase II) and protein kinase A, become activated and play critical roles in induction and maintenance of enhanced transmission. Biochemical analyses have revealed several regulated phosphorylation sites in the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits, GluR1 and GluR4. The regulated insertion of these receptors is a key event in the induction of LTP. Here, we discuss the phosphorylation of GluR1 and GluR4 and its role in receptor delivery and neuronal plasticity.

scholarly journals GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130163 ◽  
Author(s):  
Olivia A. Shipton ◽  
Ole Paulsen
Keyword(s):  
Long Term Potentiation ◽  
Subunit Composition ◽  
Current Evidence ◽  
Calcium Calmodulin Dependent ◽  
Aspartate Receptor ◽  
Term Potentiation ◽  
Dependent Protein ◽  
Nmdar Subunit ◽  
Strong Candidate

N -Methyl- d -aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses. This is owing to the interaction of GluN2B with calcium/calmodulin-dependent protein kinase II (CaMKII) and is distinct from its contribution as an ion channel.

scholarly journals Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors

2015 ◽  
Vol 112 (10) ◽  
pp. 3122-3127 ◽  
Author(s):  
Seonil Kim ◽  
Roseann F. Titcombe ◽  
Hong Zhang ◽  
Latika Khatri ◽  
Hiwot K. Girma ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Hippocampal Neurons ◽  
Gene Knockout ◽  
Long Term Potentiation ◽  
Compensatory Response ◽  
Functional Compensation ◽  
Term Potentiation ◽  
Ampar Trafficking ◽  
Dependent Protein ◽  
A Subunit

Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca2+-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca2+-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.

scholarly journals CA1 Long-Term Potentiation Is Diminished but Present in Hippocampal Slices from α-CaMKII Mutant Mice

1998 ◽  
Vol 5 (4) ◽  
pp. 344-354
Author(s):  
Heather L. Hinds ◽  
Susumu Tonegawa ◽  
Roberto Malinow
Keyword(s):  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Mutant Mice ◽  
Vitro Fertilization ◽  
Calcium Calmodulin Dependent ◽  
Term Potentiation ◽  
Significant Difference ◽  
Dependent Protein

Previous work has shown that mice missing the α-isoform of calcium–calmodulin-dependent protein kinase II (α-CaMKII) have a deficiency in CA1 hippocampal long-term potentiation (LTP). Follow-up studies on subsequent generations of these mutant mice in a novel inbred background by our laboratories have shown that whereas a deficiency in CA1 LTP is still present in α-CaMKII mutant mice, it is different both quantitatively and qualitatively from the deficiency first described. Mice of a mixed 129SvOla/SvJ;BALB/c;C57Bl/6 background derived from brother/sister mating of the α-CaMKII mutant line through multiple generations (>10) were produced by use of in vitro fertilization. Although LTP at 60 min post-tetanus was clearly deficient in these (−/−) α-CaMKII mice (42.6%, n = 33) compared with (+/+) α-CaMKII control animals (81.7%,n = 17), α-CaMKII mutant mice did show a significant level of LTP. The amount of LTP observed in α-CaMKII mutants was normally distributed, blocked by APV (2.7%, n = 8), and did not correlate with age. Although this supports a role for α-CaMKII in CA1 LTP, it also suggests that a form of α-CaMKII-independent LTP is present in mice that could be dependent on another kinase, such as the β-isoform of CaMKII. A significant difference in input/output curves was also observed between (−/−) α-CaMKII and (+/+) α-CaMKII animals, suggesting that differences in synaptic transmission may be contributing to the LTP deficit in mutant mice. However, tetani of increasing frequency (50, 100, and 200 Hz) did not reveal a higher threshold for potentiation in (−/−) α-CaMKII mice compared with (+/+) α-CaMKII controls.

Is Persistent Activity of Calcium/Calmodulin-Dependent Kinase Required for the Maintenance of LTP?

2001 ◽  
Vol 85 (4) ◽  
pp. 1368-1376 ◽  
Author(s):  
Huan-Xin Chen ◽  
Nikolai Otmakhov ◽  
Stefan Strack ◽  
Roger J. Colbran ◽  
John E. Lisman
Keyword(s):  
Protein Kinase ◽  
Experimental Tests ◽  
Long Term Potentiation ◽  
Calcium Calmodulin Dependent ◽  
Term Potentiation ◽  
Brain Extracts ◽  
Dependent Protein ◽  
Higher Temperature

Calcium/calmodulin-dependent protein kinase II (CaMKII) is concentrated in the postsynaptic density (PSD) and plays an important role in the induction of long-term potentiation (LTP). Because this kinase is persistently activated after the induction, its activity could also be important for LTP maintenance. Experimental tests of this hypothesis, however, have given conflicting results. In this paper we further explore the role of postsynaptic CaMKII in induction and maintenance of LTP. Postsynaptic application of a CaMKII inhibitor [autocamtide-3 derived peptide inhibitor (AC3-I), 2 mM] blocked LTP induction but had no detectable affect on N-methyl-d-aspartate (NMDA)-mediated synaptic transmission, indicating that the primary function of CaMKII in LTP is downstream from NMDA channel function. We next explored various methodological factors that could account for conflicting results on the effect of CaMKII inhibitors on LTP maintenance. In contrast to our previous work, we now carried out experiments at higher temperature (33°C), used slices from adult animals, and induced LTP using a tetanic stimulation. However, we still found that LTP maintenance was not affected by postsynaptic application of AC3-I. Furthermore the inhibitor did not block LTP maintenance under conditions designed to enhance the Ca2+-dependent activity of protein phosphatases 1 and 2B (elevated Ca2+, calmodulin, and an inhibitor of protein kinase A). We also tested the possibility that CaMKII inhibitor might not be able to affect CaMKII once it was inserted into the PSD. In whole-brain extracts, AC3-I blocked autophosphorylation of both soluble and particulate/PSD CaMKII with similar potencies although the potency of the inhibitor toward other CaMKII substrates varied. Thus we were unable to demonstrate a functional role of persistent Ca2+-independent CaMKII activity in LTP maintenance. Possible explanations of the data are discussed.

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