A revised view of the role of CaMKII in learning and memory.

The Ca/calmodulin (CaM)-dependent protein kinase II (CaMKII) plays a fundamental role in learning and possibly also in memory. However, current mechanistic models require fundamental revision. CaMKII autophosphorylation at Thr286 (pThr286) does not provide the molecular basis for long-term memory, as long believed.

Induction of LTP mechanisms in dually innervated dendritic spines.

Dendritic spines are the postsynaptic compartments of excitatory synapses, however, a substantial subset of spines additionally receives inhibitory input. In such dually innervated spines (DiSs), excitatory long-term potentiation (LTP) mechanisms are suppressed, but can be enabled by blocking tonic inhibitory GABA receptor signaling. Here we show that LTP mechanisms at DiSs are also enabled by two other excitatory LTP stimuli.

Studying CaMKII: Tools and standards.

The Ca/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a ubiquitous mediator of cellular Ca signals with both enzymatic and structural functions. Here, we briefly introduce the complex regulation of CaMKII and then provide a comprehensive overview of the expanding toolbox to study CaMKII. Beyond a variety of distinct mutants, these tools now include optical methods for measurement and manipulation, with the latter including light-induced inhibition, stimulation, and sequestration.

LTP induction by structural rather than enzymatic functions of CaMKII.

Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca/calmodulin-dependent protein kinase II (CaMKII). However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B.

Decreased nitrosylation of CaMKII causes aging-associated impairments in memory and synaptic plasticity in mice.

CaMKII has molecular memory functions because transient calcium ion stimuli can induce long-lasting increases in its synaptic localization and calcium ion-independent (autonomous) activity, thereby leaving memory traces of calcium ion stimuli beyond their duration. The synaptic effects of two mechanisms that induce CaMKII autonomy are well studied: autophosphorylation at threonine-286 and binding to GluN2B. Here, we examined the neuronal functions of additional autonomy mechanisms: nitrosylation and oxidation of the CaMKII regulatory domain.

Distinct synaptic pools of DAPK1 differentially regulate activity-dependent synaptic CaMKII accumulation.

The death-associated protein kinase 1 (DAPK1) regulates the synaptic movement of the Ca/calmodulin (CaM)-dependent protein kinase II (CaMKII). Synaptic CaMKII accumulation is mediated via binding to the NMDA-receptor subunit GluN2B and is required for long-term potentiation (LTP). By contrast, long-term depression (LTD) instead requires specific suppression of this movement, which is mediated by competitive DAPK1 binding to GluN2B.

Stimulating β-adrenergic receptors promotes synaptic potentiation by switching CaMKII movement from LTD to LTP mode.

Learning, memory, and cognition are thought to require synaptic plasticity, specifically including hippocampal long-term potentiation and depression (LTP and LTD). LTP versus LTD is induced by high-frequency stimulation versus low-frequency, but stimulating β-adrenergic receptors (βARs) enables LTP induction also by low-frequency stimulation (1 Hz) or theta frequencies (∼5 Hz) that do not cause plasticity by themselves. In contrast to high-frequency stimulation-LTP, such βAR-LTP requires Ca-flux through L-type voltage-gated Ca-channels, not N-methyl-D-aspartate-type glutamate receptors.

Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory in mice and is neuroprotective in pigs.

The Ca/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with the neuroprotective peptide tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories.

Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory and is neuroprotective in non-rodents.

The Ca /calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories.

Hippocampal-prefrontal theta coupling develops as mice become proficient in associative odorant discrimination learning.

Learning and memory requires coordinated activity between different regions of the brain. Here we studied the interaction between infralimbic medial prefrontal cortex (mPFC) and hippocampal dorsal CA1 during associative odorant discrimination learning in the mouse. We found that as the animal learns to discriminate odorants in a go-no go task, the coupling of high frequency neural oscillations to the phase of theta oscillations (theta-referenced phase-amplitude coupling or tPAC) changes in a manner that results in divergence between rewarded and unrewarded odorant-elicited changes in the theta-phase referenced power (tPRP) for beta and gamma oscillations.

CaMKII T286 phosphorylation has distinct essential functions in three forms of long-term plasticity.

The Ca/calmodulin-dependent protein kinase II (CaMKII) mediates long-term potentiation or depression (LTP or LTD) after distinct stimuli of hippocampal NMDA-type glutamate receptors (NMDARs). NMDAR-dependent LTD prevails in juvenile mice, but a mechanistically different form of LTD can be readily induced in adults by instead stimulating metabotropic glutamate receptors (mGluRs). However, the role that CaMKII plays in the mGluR-dependent form of LTD is not clear.

Peripheral eosinophil count and eosinophil-to-lymphocyte ratio are associated with revision sinus surgery.

Purpose: The aim of this study was to assess whether hematological indices of the peripheral blood are associated with revision surgery in patients with chronic rhinosinusitis (CRS) undergoing endoscopic sinus surgery (ESS).

Methods: This retrospective, cross-sectional, single-center study included 541 CRS patients that underwent ESS. Demographics and laboratory parameters were retrieved, and group comparisons were performed.

Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events.

Aβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that Aβ could have a similar effect. Notably, Aβ impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly into holoenzymes. Furthermore, this Aβ-induced impairment is prevented by CaMKII inhibitors that should also inhibit the putative direct Aβ binding.

Factors Associated with Revision Sinus Surgery in Patients with Chronic Rhinosinusitis.

Endoscopic sinus surgery (ESS) is performed in patients diagnosed with Chronic Rhinosinusitis (CRS) refractory to primary medical therapy to achieve adequate disease control. This study aimed to assess which factors and phenotypes of CRS are associated with revision surgery in patients undergoing ESS. This retrospective, single-center study included 667 patients undergoing ESS between 2012 and 2015.

Functional Brain Changes Due to Chronic Abdominal Pain in Inflammatory Bowel Disease: A Case-Control Magnetic Resonance Imaging Study.

Introduction: Various chronic pain conditions go along with functional and structural brain changes. This study aimed to investigate functional and structural brain changes by magnetic resonance imaging (MRI) in inflammatory bowel disease (IBD) patients with chronic abdominal pain.

Methods: Sixty-four subjects were included in the final analysis (32 IBD patients with chronic abdominal pain; 32 age-matched and sex-matched controls).

Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly.

Neuronal CaMKII holoenzymes (α and β isoforms) enable molecular signal computation underlying learning and memory but also mediate excitotoxic neuronal death. Here, we provide a comparative analysis of these signaling devices, using single-particle electron microscopy (EM) in combination with biochemical and live-cell imaging studies. In the basal state, both isoforms assemble mainly as 12-mers (but also 14-mers and even 16-mers for the β isoform).

GluN2B S1303 phosphorylation by CaMKII or DAPK1: no indication for involvement in ischemia or LTP.

Binding of two different CaM kinases, CaMKII and DAPK1, to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B near S1303 has been implicated in excitotoxic/ischemic neuronal cell death. The GluN2B mutation (L1298A, R1300Q) is neuroprotective but abolishes only CaMKII but not DAPK1 binding. However, both kinases can additionally phosphorylate GluN2B S1303.

CaMKIIα knockout protects from ischemic neuronal cell death after resuscitation from cardiac arrest.

CaMKIIα plays a dual role in synaptic plasticity, as it can mediate synaptic changes in opposing directions. We hypothesized that CaMKIIα plays a similar dual role also in neuronal cell death and survival. Indeed, the CaMKII inhibitor tatCN21 is neuroprotective when added during or after excitotoxic/ischemic insults, but was described to cause sensitization when applied long-term prior to such insult.

Characterization of six CaMKIIα variants found in patients with schizophrenia.

The Ca/Calmodulin-dependent protein kinase II (CaMKII) is a central regulator of synaptic plasticity and has been implicated in various neurological conditions, including schizophrenia. Here, we characterize six different CaMKIIα variants found in patients with schizophrenia. Only R396stop disrupted the 12-meric holoenzyme structure, GluN2B binding, and synaptic localization.

Bitter Taste Disrupts Spatial Discrimination of Piperine-Evoked Burning Sensations: A Pilot Study.

This study aimed to investigate the perceptual similarity between piperine-induced burning sensations and bitter taste using piperine-impregnated taste strips (PTS). This pilot study included 42 healthy participants. PTS of six ascending concentrations (1 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg piperine/dL 96% ethanol) were presented at the anterior tongue, and participants rated perceived intensity and duration.

Young DAPK1 knockout mice have altered presynaptic function.

The death-associated protein kinase 1 (DAPK1) has recently been shown to have a physiological function in long-term depression (LTD) of glutamatergic synapses: acute inhibition of DAPK1 blocked the LTD that is normally seen at the hippocampal CA1 synapse in young mice, and a pharmacogenetic combination approach showed that this specifically required DAPK1-mediated suppression of postsynaptic Ca/calmodulin-dependent protein kinase II binding to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B during LTD stimuli. Surprisingly, we found here that genetic deletion of DAPK1 (in DAPK1 mice) did not reduce LTD. Paired pulse facilitation experiments indicated a presynaptic compensation mechanism: in contrast to wild-type mice, LTD stimuli in DAPK1 mice decreased presynaptic release probability.

CaMKII holoenzyme mechanisms that govern the LTP versus LTD decision.

Higher brain functions are thought to require synaptic frequency decoding that can lead to long-term potentiation (LTP) or depression (LTD). We show that the LTP versus LTD decision is determined by complex cross-regulation of T286 and T305/306 autophosphorylation within the 12meric CaMKII holoenzyme, which enabled molecular computation of stimulus frequency, amplitude, and duration. Both LTP and LTD require T286 phosphorylation, but T305/306 phosphorylation selectively promoted LTD.

Determination of the molecular reach of the protein tyrosine phosphatase SHP-1.

Immune receptors signal by recruiting (or tethering) enzymes to their cytoplasmic tails to catalyze reactions on substrates within reach. This is the case for the phosphatase SHP-1, which, upon tethering to inhibitory receptors, dephosphorylates diverse substrates to control T cell activation. Precisely how tethering regulates SHP-1 activity is incompletely understood.