Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector, acts as a graded switch for memory formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10-100 Hz. These mice exhibit superior ability in learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation. NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.

Acid Sensing Ion Channels (ASICs) are a group of sodium-selective ion channels that are activated by low extracellular pH. The role of ASIC in disease states remains unclear partly due to the lack of selective pharmacological agents. In this report, we describe the effects of A-317567, a novel non-amiloride blocker, on three distinct types of native ASIC currents evoked in acutely dissociated adult rat dorsal root ganglion (DRG) neurons. A-317567 produced concentration-dependent inhibition of all pH 4.5-evoked ASIC currents with an IC50 ranging between 2 and 30muM, depending upon the type of ASIC current activated. Unlike amiloride, A-317567 equipotently blocked the sustained phase of ASIC3-like current, a biphasic current akin to cloned ASIC3, which is predominant in DRG. When evaluated in the rat Complete Freud's Adjuvant (CFA)-induced inflammatory thermal hyperalgesia model, A-317567 was fully efficacious at a dose 10-fold lower than amiloride. A-317567 was also potent and fully efficacious when tested in the skin incision model of post-operative pain. A-317567 was entirely devoid of any diuresis or natriuresis activity and showed minimal brain penetration. In summary, A-317567 is the first reported small molecule non-amiloride blocker of ASIC that is peripherally active and is more potent than amiloride in vitro and in vivo pain models. The discovery of A-317567 will greatly help to enhance our understanding of the physiological and pathophysiological role of ASICs.

Postsynaptic differentiation during glutamatergic synapse formation is poorly understood. Using a novel biophysical approach, we have investigated the distribution and density of functional glutamate receptors and characterized their clustering during synaptogenesis in cultured hippocampal neurons. We found that functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors are evenly distributed in the dendritic membrane before synaptogenesis with an estimated density of 3 receptors/microm(2). Following synaptogenesis, functional AMPA and NMDA receptors are clustered at synapses with a density estimated to be on the order of 10(4) receptors/microm(2), which corresponds to approximately 400 receptors/synapse. Meanwhile there is no reduction in the extrasynaptic receptor density, which indicates that the aggregation of the existing pool of receptors is not the primary mechanism of glutamate receptor clustering. Furthermore our data suggest that the ratio of AMPA to NMDA receptor density may be regulated to be close to one in all dendritic locations. We also demonstrate that synaptic AMPA and NMDA receptor clusters form with a similar time course during synaptogenesis and that functional AMPA receptors cluster independently of activity and glutamate receptor activation, including following the deletion of the NMDA receptor NR1 subunit. Thus glutamate receptor activation is not necessary for the insertion, clustering, and activation of functional AMPA receptors during synapse formation, and this process is likely controlled by an activity-independent signal.

Acid Sensing Ion Channels (ASICs) are a family of cation channels expressed principally in neurons and that are activated by protons. The sensitivity of ASICs to acidosis and their distribution in primary sensory neurons points to a significant role of these channels in acid nociception. However, despite the fact that the first ASIC was identified more than 10 years ago the physiological and pathophysiological role of this channel family remains poorly understood. In this paper, the available body of data (genetic, pharmacological, and other) on ASICs will be reviewed and the role of ASIC in normal nociception and other pain sensations will be discussed. Some of the recent drug discovery and development activities ongoing in our laboratory, which point to ASICs being a relevant target for pain modulation, will also be summarized.

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