This Week in The Journal

Cellular/Molecular

Keeping CaMKII at the Synapse

K. Ulrich Bayer, Éric LeBel, Greg L. McDonald, Heather O’Leary, Howard Schulman, and Paul De Koninck

Ca²⁺/calmodulin (CaM)-dependent kinase (CaMKII) and the NMDA receptor subunit NR2B are established contributors to synaptic plasticity. This week, Bayer et al. show that the activity- and NMDA-receptor-dependent translocation of CaMKII to the synapse has two phases. In cultured hippocampal neurons, persistent translocation of GFP (green fluorescent protein)-labeled CaMKII to synapses depended on NMDA receptor activation but not on CaMKII autophosphorylation at the T286 site. Using site-directed mutagenesis, the authors document a two-phase binding scheme whereby transient activity elicited Ca²⁺/CaM-dependent binding of NR2B to CaMKII at its substrate-binding site (“S-site”), whereas prolonged activity led to persistent binding at the T286-binding site (“T-site”). This interaction prevented binding of the regulatory region, thus creating a second mechanism (in addition to autophosphorylation) that allows sustained CaMKII activity and compartmentalization at synapses. Although Ca²⁺/CaM was not required for the T-site binding, it may speed the transition.⇓

The NR2B-binding surface on CaMKII is shown with residues implicated in the interaction with the autoregulatory domain. The “S-site” and “T-site” are shown in orange and yellow, respectively. See the article by Bayer et al. for details.

Development/Plasticity/Repair

A Bloodless Role for the Erythropoietin Receptor

Peter T. Tsai, John Ohab, Nathalie Kertesz, Matthias Groszer, Cheryl Matter, Jing Gao, Xin Liu, Hong Wu, and S. Thomas Carmichael

(see pages 1269–1274)

Although named for its effect on red cell production and made infamous by “blood doping” in athletes, the growth factor erythropoietin (EPO) and its receptor (EPOR) also provide important signaling in brain. In this week’s Journal, Tsai et al. examined the role of endogenous EPO and EPOR in neurogenesis. Deletion of either the Epo or EpoR gene resulted in similar effects: incomplete neural tube closure at embryonic day 10.5 (E10.5) and severe neurogenic defects by E13.5. Thus, the authors surmised that the EPOR was essential for EPO-mediated developmental neurogenesis. Using the loxp/Cre system, they created conditional knock-down mice that lacked brain EPOR expression after E14. The mutant mice had fewer cells in the subventricular zone at postnatal day 15 and at 6 months. After ischemic injury in a focal stroke model, EPOR did not afford neuroprotection. Rather, EPOR-deficient poststroke mice displayed reduced neurogenesis because of impaired neuroblast migration.

Behavioral/Systems/Cognitive

Modeling Perceptual Decisions

Kong-Fatt Wong and Xiao-Jing Wang

(see pages 1314–1328)

Making decisions can be tough and can take considerable time, at least for some of us. Several groups have examined perceptual decision making in primates using forced-choice visual motion discrimination tasks. On these tasks, firing in the lateral intraparietal cortex (LIP) correlates with the reaction time and the correctness of the choice. This activity builds over several hundred milliseconds, suggesting that LIP could be integrating information before a decision. This week, Wang and Wong built a spiking-neuron network model that was able to mimic these activity patterns. The model was based on a previous network model including thousands of neurons, but the authors used a reduced version containing only two dynamical variables. Despite the simplifications and assumptions, the model revealed useful insights. Reverberant excitation mediated by NMDA receptors was critical for the slow time integration. The model also explained the experimentally observed longer reaction time in error trials compared with correct trials.

Neurobiology of Disease

Painful Action Potentials

Laiche Djouhri, Stella Koutsikou, Xin Fang, Simon McMullan, and Sally N. Lawson

(see pages 1281–1292)

Neuropathic pain is characterized by shooting, burning, stabbing, and electrical sensations that are thought to arise from spontaneous activity of injured afferent nerves. This week, Djouhri et al. recorded spontaneous foot lifting as an indicator of spontaneous pain in nerve-injured rats. Spinal nerve axotomy (SNA) of L5 did not evoke spontaneous foot lifting, but a modified SNA (mSNA) procedure did. In addition to L5 axotomy, the mSNA involved loose ligation of the adjacent L4 spinal nerve with chromic gut, providing a key inflammatory component. Another group of animals was injected with complete Freund’s adjuvant, causing peripheral inflammation. Using intracellular recordings from ipsilateral L4 dorsal root ganglion neurons, the authors found that spontaneous firing rate of intact C-type nociceptive neurons correlated with spontaneous foot lifting. The results suggest that both neuropathic pain and spontaneous firing depend on an inflammatory component, at least in this model system.