Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca
            <sup>2+</sup>
            -permeable AMPA receptors

a b s t r a c tReggie-1 and -2 (flotillins) reside at recycling vesicles and promote jointly with Rab11a the targeted delivery of cargo. Recycling is essential for synapse formation suggesting that reggies and Rab11a may regulate the development of spine synapses. Recycling vesicles provide cargo for dendritic growth and recycle surface glutamate receptors (AMPAR, GluA) for long-term potentiation (LTP) induced surface exposure. Here, we show reduced number of spine synapses and impairment of an in vitro correlate of LTP in hippocampal neurons from reggie-1 k.o. (Flot2−/−) mice maturating in culture. These defects apparently result from reduced trafficking of PSD-95 revealed by live imaging of 10 div reggie-1 k.o. (Flot2 −/−) neurons and likely impairs co-transport of cargo destined for spines: N-cadherin and the glutamate receptors GluA1 and GluN1. Impaired cargo trafficking and fewer synapses also emerged in reggie-1 siRNA, reggie-2 siRNA, and reggie-1 and -2 siRNA-treated neurons and was in siRNA and k.o. neurons rescued by reggie-1-EGFP and CA-Rab11a-EGFP. While correlative expressional changes of specific synapse proteins were observed in reggie-1 k.o. (Flot2−/−) brains in vivo, this did not occur in neurons maturating in vitro. Our work suggests that reggie-1 and reggie-2 function at Rab11a recycling containers in the transport of PSD-95, N-cadherin, GluA1 and GluN1, and promote (together with significant signaling molecules) spine-directed trafficking, spine synapse formation and the in vitro correlate of LTP.

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“…cGKII k.o. mice showed no impairment of LTP whereas LTP was impaired when cGKII was acutely inhibited (Kim et al, 2015). The LTP in k.o.…”

Section: Discussionmentioning

confidence: 88%

Reggie-1 and reggie-2 (flotillins) participate in Rab11a-dependent cargo trafficking, spine synapse formation and LTP-related AMPA receptor (GluA1) surface exposure in mouse hippocampal neurons

Bodrikov

Pauschert

Kochlamazashvili

et al. 2017

Experimental Neurology

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“…We showed in a previous study that functional compensation occurs in the hippocampus, and synaptic GluA1-pS845 levels are increased in cGKII KO mice compared with WT littermates (Kim et al 2015a). We wanted to examine whether this functional compensation via increased GluA1-pS845 in the hippocampus had a different behavioral effect than the reduced GluA1-pS845 levels we observed in the amygdala (Fig.…”

Section: Amygdala-dependent Auditory Cued Fear Conditioning Is Impairmentioning

confidence: 78%

“…Although cGKII is important for GluA1-pS845 and LTP (Serulle et al 2007), cGKII knockout (KO) shows functional compensation in the hippocampus via the calcineurin-mediated homeostatic mechanism (Kim et al 2015a). In the KO hippocampus, synaptic GluA1-pS845 is increased, expressing GluA2-lacking Ca 2+ -permeable AMPARs, which provides a novel form of LTP as a compensatory response to the genetic deletion of cGKII (Kim et al 2015a).…”

mentioning

confidence: 99%

“…In the KO hippocampus, synaptic GluA1-pS845 is increased, expressing GluA2-lacking Ca 2+ -permeable AMPARs, which provides a novel form of LTP as a compensatory response to the genetic deletion of cGKII (Kim et al 2015a). However, we have shown that this compensation is restricted to the hippocampus since GluA1-pS845 is significantly reduced in the prefrontal cortex (PFC) (Wincott et al 2013).…”

mentioning

confidence: 99%

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Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

et al. 2016

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Phosphorylation of GluA1, a subunit of AMPA receptors (AMPARs), is critical for AMPAR synaptic trafficking and control of synaptic transmission. cGMP-dependent protein kinase II (cGKII) mediates this phosphorylation, and cGKII knockout (KO) affects GluA1 phosphorylation and alters animal behavior. Notably, GluA1 phosphorylation in the KO hippocampus is increased as a functional compensation for gene deletion, while such compensation is absent in the prefrontal cortex. Thus, there are brain region-specific effects of cGKII KO on AMPAR trafficking, which could affect animal behavior. Here, we show that GluA1 phosphorylation levels differ in various brain regions, and specific behaviors are altered according to region-specific changes in GluA1 phosphorylation. Moreover, we identified distinct regulations of phosphatases in different brain regions, leading to regional heterogeneity of GluA1 phosphorylation in the KO brain. Our work demonstrates region-specific changes in GluA1 phosphorylation in cGKII KO mice and corresponding effects on cognitive performance. We also reveal distinct regulation of phosphatases in different brain region in which region-specific effects of kinase gene KO arise and can selectively alter animal behavior.

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“…Compensatory effects in mutant mice are a common limitation of genetic approaches (26 -28). For instance, normal hippocampal LTP in cyclic GMP-dependent kinase II knockout mice is enabled by increased Ca 2ϩ -permeable AMPA receptor function (28). In an extreme example, normal physiological LTP is clearly mediated by changes in AMPA receptor currents, yet LTP can still be induced in neurons in which AMPA receptors are completely eliminated, and kainate receptors that are not normally found at these synapses are expressed instead (29).…”

Section: Discussionmentioning

confidence: 99%

The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength

Barcomb¹,

Hell

Benke

et al. 2016

Journal of Biological Chemistry

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Learning, memory, and cognition are thought to require normal long-term potentiation (LTP) of synaptic strength, which in turn requires binding of the Ca 2؉ /calmodulin-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B. For LTP induction, many additional required players are known. Here we tested the hypothesis that CaMKII/GluN2B binding also mediates the more elusive maintenance of synaptic strength. Intriguingly, the CaMKII inhibitor tatCN21 reduces synaptic strength only at high concentrations necessary for CaMKII/NMDAR disruption (20 M) but not at lower concentrations sufficient for kinase inhibition (5 M). However, increased concentration also causes unrelated effects. Thus, to distinguish between correlation and causality, we used a pharmacogenetic approach. In a mouse with a mutant NMDAR GluN2B subunit that is CaMKII binding-incompetent, any tatCN21 effects that are specific to the CaMKII/GluN2B interaction should be abolished, and any remaining tatCN21 effects have to be nonspecific (i.e. mediated by other targets). The results showed that the persistent reduction of synaptic strength by transient application of 20 M tatCN21 had a nonspecific presynaptic component (on fiber volley amplitude) that was unrelated to the CaMKII/GluN2B interaction or CaMKII activity. However, the remaining component of the persistent tatCN21 effect was almost completely abolished in the GluN2B mutant mouse. These results highlight the requirement for stringent pharmacogenetic approaches to separate specific ontarget effects from nonspecific off-target effects. Importantly, they also demonstrate that the CaMKII/GluN2B interaction is required not only for normal LTP induction but also for the maintenance of synaptic strength.The Ca 2ϩ /calmodulin-dependent protein kinase II (CaM-KII) 3 and the NMDA-type glutamate receptor (NMDAR) are central mediators of long-term potentiation (LTP) and depression (LTD), forms of synaptic plasticity thought to underlie learning, memory, and cognition (1; for a review, see Refs. 2-5). Many additional molecular players have been implicated in the induction of these changes of synaptic strength (4, 6, 7); however, the mechanisms responsible for then maintaining synaptic strength have been elusive. CaMKII has been hypothesized to mediate not only LTP induction but also the maintenance of synaptic strength (2-4), as Ca 2ϩ influx through NMDARs triggers CaMKII autophosphorylation at Thr-286 to generate Ca 2ϩ -independent "autonomous" kinase activity, a process that can provide "molecular memory" of the initial Ca 2ϩ stimulus (8, 9). However, although CaMKII Thr-286 phosphorylation is indeed required for LTP (10), this requirement is for induction rather than maintenance. Thr-286 phosphorylation of synaptic CaMKII is reversed within 2 min of LTP induction (11), and CaMKII inhibition after LTP induction does not affect maintenance (9). Another kinase that has received prominent attention as a "memory kinase" is PKM, and its inhibitor myrZIP does indeed reve...

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Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors

Cited by 41 publications

References 49 publications

Reggie-1 and reggie-2 (flotillins) participate in Rab11a-dependent cargo trafficking, spine synapse formation and LTP-related AMPA receptor (GluA1) surface exposure in mouse hippocampal neurons

Reggie-1 and reggie-2 (flotillins) participate in Rab11a-dependent cargo trafficking, spine synapse formation and LTP-related AMPA receptor (GluA1) surface exposure in mouse hippocampal neurons

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength

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Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca 2+ -permeable AMPA receptors

Cited by 41 publications

References 49 publications

Reggie-1 and reggie-2 (flotillins) participate in Rab11a-dependent cargo trafficking, spine synapse formation and LTP-related AMPA receptor (GluA1) surface exposure in mouse hippocampal neurons

Reggie-1 and reggie-2 (flotillins) participate in Rab11a-dependent cargo trafficking, spine synapse formation and LTP-related AMPA receptor (GluA1) surface exposure in mouse hippocampal neurons

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength

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Product

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Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca ²⁺ -permeable AMPA receptors