A. Soren Leonard

Interaction with the NMDA receptor locks CaMKII in an active conformation

Calcium- and calmodulin-dependent protein kinase II (CaMKII) and glutamate receptors are integrally involved in forms of synaptic plasticity that may underlie learning and memory. In the simplest model for long-term potentiation, CaMKII is activated by Ca2+ influx through NMDA (N-methyl-d-aspartate) receptors and then potentiates synaptic efficacy by inducing synaptic insertion and increased single-channel conductance of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Here we show that regulated CaMKII interaction with two sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons. This interaction can lead to additional forms of potentiation by: facilitated CaMKII response to synaptic Ca2+; suppression of inhibitory autophosphorylation of CaMKII; and, most notably, direct generation of sustained Ca2+/calmodulin (CaM)-independent (autonomous) kinase activity by a mechanism that is independent of the phosphorylation state. Furthermore, the interaction leads to trapping of CaM that may reduce down-regulation of NMDA receptor activity. CaMKII–NR2B interaction may be prototypical for direct activation of a kinase by its targeting protein.

Contribution of Drosophila DEG/ENaC Genes to Salt Taste

The ability to detect salt is critical for the survival of terrestrial animals. Based on amiloride-dependent inhibition, the receptors that detect salt have been postulated to be DEG/ENaC channels. We found the Drosophila DEG/ENaC genes Pickpocket11 (ppk11) and Pickpocket19 (ppk19) expressed in the larval taste-sensing terminal organ and in adults on the taste bristles of the labelum, the legs, and the wing margins. When we disrupted PPK11 or PPK19 function, larvae lost their ability to discriminate low concentrations of Na(+) or K(+) from water, and the electrophysiologic responses to low salt concentrations were attenuated. In both larvae and adults, disrupting PPK11 or PPK19 affected the behavioral response to high salt concentrations. In contrast, the response of larvae to sucrose, pH 3, and several odors remained intact. These results indicate that the DEG/ENaC channels PPK11 and PPK19 play a key role in detecting Na(+) and K(+) salts.

cAMP-dependent protein kinase phosphorylation of the acid-sensing ion channel-1 regulates its binding to the protein interacting with C-kinase-1

The acid-sensing ion channel-1 (ASIC1) contributes to synaptic plasticity and may influence the response to cerebral ischemia and acidosis. We found that cAMP-dependent protein kinase phosphorylated heterologously expressed ASIC1 and endogenous ASIC1 in brain slices. ASIC1 also showed significant phosphorylation under basal conditions. Previous studies showed that the extreme C-terminal residues of ASIC1 bind the PDZ domain of the protein interacting with C-kinase-1 (PICK1). We found that protein kinase A phosphorylation of Ser-479 in the ASIC1 C terminus interfered with PICK1 binding. In contrast, minimizing phosphorylation or mutating Ser-479 to Ala enhanced PICK1 binding. Phosphorylation-dependent disruption of PICK1 binding reduced the cellular colocalization of ASIC1 and PICK1. Thus, the ASIC1 C terminus contains two sites that influence its binding to PICK1. Regulation of this interaction by phosphorylation provides a mechanism to control the cellular localization of ASIC1.

Knock-in mouse model of alternating hemiplegia of childhood: Behavioral and electrophysiologic characterization

Mutations in the ATP1α3 subunit of the neuronal Na+/K+‐ATPase are thought to be responsible for seizures, hemiplegias, and other symptoms of alternating hemiplegia of childhood (AHC). However, the mechanisms through which ATP1A3 mutations mediate their pathophysiologic consequences are not yet understood. The following hypotheses were investigated: (1) Our novel knock‐in mouse carrying the most common heterozygous mutation causing AHC (D801N) will exhibit the manifestations of the human condition and display predisposition to seizures; and (2) the underlying pathophysiology in this mouse model involves increased excitability in response to electrical stimulation of Schaffer collaterals and abnormal predisposition to spreading depression (SD).

Does Epileptiform Activity Contribute to Cognitive Impairment in Alzheimer's Disease?

Alzheimers disease is a devastating neurological disorder. The role of hyperexcitability in the diseases cognitive decline is not completely understood. In this issue of Neuron, Palop et al. report both limbic seizures and presumed homeostatic responses to seizures in an animal model of Alzheimers.

Potential neuroprotective effects of continuous topiramate therapy in the developing brain.

Because antiepileptic drug therapy is usually given chronically with resulting concerns about long-term neurotoxicity, and because short-term topiramate (TPM) therapy has been reported to be neuroprotective against the effects of acute hypoxia, we investigated the long-term effects of continuous TPM therapy during early stages of development. Four groups of rat pups were studied: two sham manipulated normoxia groups and two acute hypoxia groups (at postnatal day [P] 10 down to 4% O(2)), each injected intraperitoneally daily with either vehicle or TPM (30 mg/kg) from P0 to P21. TPM therapy prevented hypoxia-induced long-term (P81) memory impairment (Morris water maze) as well as aggressivity (handling test). The hypoxia group receiving TPM also showed a trend toward reduced CA1 hippocampal cell loss. The aforementioned TPM therapy had no long-term deleterious effects on memory, hyperactivity, or CA1 cell counts in the TPM normoxia group as compared with normal controls.

Seizure predisposition after perinatal hypoxia: Effects of subsequent age and of an epilepsy predisposing gene mutation

There is a gap in our knowledge of the factors that modulate the predisposition to seizures following perinatal hypoxia. Herein, we investigate in a mouse model the effects of two distinct factors: developmental stage after the occurrence of the perinatal insult, and the presence of a seizure predisposing mutation.

Conditional deletion of TrkC does not modify limbic epileptogenesis

The neurotrophin receptor, tropomyosin-related kinase B (TrkB), is required for epileptogenesis in the kindling model. The role of a closely related neurotrophin receptor, TrkC, in limbic epileptogenesis is unknown. We examined limbic epileptogenesis in the kindling model in TrkC conditional null mice, using a strategy that previously established a critical role of TrkB. Despite elimination of TrkC mRNA, no differences in development of kindling were detected between TrkC conditional null and wild type control mice. These findings reinforce the central role of TrkB as the principal neurotrophin receptor involved in limbic epileptogenesis.

What Is Their Fate after Magnesium Sulfate

ing that there is a clear developmental window for the susceptibility of MgSO 4 exposure. MgSO 4 has been considered an effective tocolytic agent for decades. Nevertheless, some studies have reported harmful fetal and neonatal effects with MgSO 4 . The most recent review of the Cochrane registry indicates that magnesium sulfate does have positive neuroprotective effects in the newborn [2] . On the other hand, this review also points out that the full effects of this therapy are still not known and it highlights the need to examine later in childhood the outcomes of infants whose mothers received MgSO 4 so as to determine the presence of potential latent neurological effects. It has long been presumed that administration of MgSO 4 is neuroprotective through reducing NMDA receptor Ca 2+ influx. However, NMDA can promote cell survival as well as cell death [3] . As illustrated in Dribben’s article, predicting the precise outcome is not easily done since the above depends on the magnitude of NMDA activation, on the specific area of the brain, and on age. In cultured neurons, magnesium levels can have both positive and negative effects depending We read with interest the recent article by Dribben et al. [1] , which we believe is important and has several implications. Firstly, this article demonstrates that the effects of magnesium sulfate are ageand model-dependent. This raises the question as to whether the effects of MgSO 4 on the eclamptic mother’s brain and on the newborn infant’s brain are different, thereby indicating that further studies to address this question are needed. In addition, it suggests that the effects on the extremely premature, premature, and full-term brain may also be different. Secondly, this study demonstrates specific effects of magnesium sulfate on cell survival and death pathways and strongly suggests that further studies investigating the mechanisms of the effects of this agent on neuronal tissues are needed. Dribben et al. demonstrated that the treatment of P3–P7 mice with MgSO 4 increased neurodegeneration via increased apoptosis. There were various regions affected by this treatment; however, the number of cells undergoing MgSO 4 -induced apoptosis generally decreased with age. Accordingly, at P14 only the hippocampus exhibited an elevated number of apoptotic neurons, thereby demonstratReceived: November 23, 2009 Accepted after revision: December 18, 2009 Published online: March 16, 2010