CaMK2N1 and CaMK2N2 are endogenous inhibitors of calcium/calmodulin-dependent protein kinase II (CaMKII), a key synaptic signaling molecule for learning and memory. Here, we investigated the learning and memory function of CaMK2N1 by knocking-down its expression in dorsal hippocampus of mice. We found that reduced CaMK2N1 expression does not affect contextual fear long-term memory (LTM) formation. However, we show that it impairs maintenance of established LTM, but only if retrieval occurs. CaMK2N1 knockdown prevents a decrease of threonine-286 (T286) autophosphorylation of αCaMKII and increases GluA1 levels in hippocampal synapses after retrieval of contextual fear LTM. CaMK2N1 knockdown can also increase CaMK2N2 expression, but we show that such increased expression does not affect LTM after retrieval. We also found that substantial overexpression of CaMK2N2 in dorsal hippocampus impairs LTM formation, but not LTM maintenance, suggesting that CaMKII activity is not required for LTM storage. Taken together, we propose a specific function for CaMK2N1; enabling LTM maintenance after retrieval by inhibiting T286 autophosphorylation of αCaMKII.

Nearly three million people in the USA suffer traumatic brain injury (TBI) yearly; however, there are no pre- or post-TBI treatment options available. KCNQ2-5 voltage-gated K+ channels underlie the neuronal “M current”, which plays a dominant role in the regulation of neuronal excitability. Our strategy towards prevention of TBI-induced brain damage is predicated on the suggested hyper-excitability of neurons induced by TBIs, and the decrease in neuronal excitation upon pharmacological augmentation of M/KCNQ K+ currents. Seizures are very common after a TBI, making further seizures and development of epilepsy disease more likely. Our hypothesis is that TBI-induced hyperexcitability and ischemia/hypoxia lead to metabolic stress, cell death and a maladaptive inflammatory response that causes further downstream morbidity. Using the mouse controlled closed-cortical impact blunt TBI model, we found that systemic administration of the prototype M-channel “opener”, retigabine (RTG), 30 min after TBI, reduces the post-TBI cascade of events, including spontaneous seizures, enhanced susceptibility to chemo-convulsants, metabolic stress, inflammatory responses, blood–brain barrier breakdown, and cell death. This work suggests that acutely reducing neuronal excitability and energy demand via M-current enhancement may be a novel model of therapeutic intervention against post-TBI brain damage and dysfunction.

Repetitive blast traumatic brain injury (TBI) affects numerous soldiers on the battlefield. Mild TBI has been shown to have long-lasting effects with repeated injury. We have investigated effects on neuronal excitability after repetitive, mild TBI in a mouse model of blast-induced brain injury. We exposed mice to mild blast trauma of an average peak overpressure of 14.6 psi, repeated across three consecutive days. While a single exposure did not reveal trauma as indicated by the glial fibrillary acidic protein indicator, three repetitive blasts did show significant increases. As well, mice had an increased indicator of inflammation (Iba-1) and increased tau, tau phosphorylation, and altered cytokine levels in the spleen. Videoelectroencephalographic monitoring 48 h after the final blast exposure demonstrated seizures in 50% (12/24) of the mice, most of which were non-convulsive seizures. Long-term monitoring revealed that spontaneous seizures developed in at least 46% (6/13) of the mice. Patch clamp recording of dentate gyrus hippocampus neurons 48 h post-blast TBI demonstrated a shortened latency to the first spike and hyperpolarization of action potential threshold. We also found that evoked excitatory postsynaptic current amplitudes were significantly increased. These findings indicate that mild, repetitive blast exposures cause increases in neuronal excitability and seizures and eventual epilepsy development in some animals. The non-convulsive nature of the seizures suggests that subclinical seizures may occur in individuals experiencing even mild blast events, if repeated.

K v 7 ("M-type," KCNQ) K + currents, play dominant roles in controlling neuronal excitability. They act as a "brake" against hyperexcitable states in the central and peripheral nervous systems. Pharmacological augmentation of M current has been developed for controlling epileptic seizures, although current pharmacological tools are uneven in practical usefulness. Lately, however, M-current "opener" compounds have been suggested to be efficacious in preventing brain damage after multiple types of insults/diseases, such as stroke, traumatic brain injury, drug addiction and mood disorders. In this review, we will discuss what is known to date on these efforts and identify gaps in our knowledge regarding the link between M current and therapeutic potential for these disorders. We will outline the preclinical experiments that are yet to be performed to demonstrate the likelihood of success of this approach in human trials. Finally, we also address multiple pharmacological tools available to manipulate different K v 7 subunits and the relevant evidence for translational application in the clinical use for disorders of the central nervous system and multiple types of brain insults. We feel there to be great potential for manipulation of K v 7 channels as a novel therapeutic mode of intervention in the clinic, and that the paucity of existing therapies obligates us to perform further research, so that patients can soon benefit from such therapeutic approaches.

In this review, we discuss the poorly explored role of calcium/calmodulin‐dependent protein kinase II (CaMKII) in memory maintenance, and its influence on memory destabilization. After a brief review on CaMKII and memory destabilization, we present critical pieces of evidence suggesting that CaMKII activity increases retrieval‐induced memory destabilization. We then proceed to propose two potential molecular pathways to explain the association between CaMKII activation and increased memory destabilization. This review will pinpoint gaps in our knowledge and discuss some ‘controversial’ observations, establishing the basis for new experiments on the role of CaMKII in memory reconsolidation. The role of CaMKII in memory destabilization is of great clinical relevance. Still, because of the lack of scientific literature on the subject, more basic science research is necessary to pursue this pathway as a clinical tool.