Positive allosteric modulators of α-amino-3-hydroxyl-5-methyl-4-isoxazole- propionate (AMPA)–type glutamate receptors (“ampakines” and functionally related compounds) constitute a relatively new class of psychoactive drugs that enhance fast, excitatory transmission in the brain. Because of this effect, ampakines reduce the threshold for inducing memoryrelated changes to synapses and improve learning in animals across species and paradigms. While most CNS drugs target neurons that project in a onestep, parallel fashion to a multitude of sites, ampakine-type agents act on the multiple connections found in serial brain networks. This results in a multiplier effect for the drug, likely to be most pronounced in the elaborate circuits found in the cortex, thereby intensifying cortical regulation of lower brain areas (“pharmacological encephalization”). Evidence that the compounds are effective in animal models of psychiatric disorders associated with abnormal brainstem activity is in agreement with this hypothesis. The possibility that expanding cortical networks will lead to cognitive, as opposed to memory, enhancement in normal brains is largely unexplored. Finally, positive modulators increase the production of brain growth factors that promote plasticity and neuronal viability; upregulation is associated with neuroprotection, growth, and improved functional outcomes in different disease models.

Exposure to low temperature causes platelets to change shape in a manner similar to the shape change that precedes secretagogue-induced serotonin release. Previous studies have shown that two proteins, of approximately 20,000 and approximately 40,000 Mr, become phosphorylated before secretion. We have investigated whether low temperature can induce phosphorylation of these proteins and/or serotonin secretion. The data indicate that low-temperature-induced shape change has no requirement for extracellular calcium, whereas phosphorylation of the two proteins and subsequent serotonin release both have strong calcium requirements. Because cold treatment is thought to influence platelet shape through an effect on microtubules, the events in the shape change-release sequence would seem to be ordered as follows: microtubule disassembly leads to shape change leads to protein phosphorylation leads to secretion.

A kinetic model of the glutamate DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor/channel complex was used to test whether changes in the rate constants describing channel behavior could account for various features of long-term potentiation (LTP). Starting values for the kinetic parameters were set to satisfy experimental data (e.g., affinity, mean open time, mean burst length, etc.) and physical constraints (i.e., microreversibility). The resultant model exhibited a variety of dynamic properties known to be associated with the receptor. Increasing the rate constants governing opening/closing of the channel produced an unexpected increase in the probability of the channel being open shortly after transmitter binding. This would account for the enhanced response size with LTP. Increases in rate constants produced two other aspects of LTP: (i) an alteration of the waveform of the synaptic response and (ii) an interaction with changes in desensitization kinetics. The results obtained with the model corresponded closely to those found in LTP experiments. Thus, an increase in opening/closing rates for the postsynaptic receptor channel provides a single explanation for diverse characteristics of LTP. Finally, the kinetic manipulation reduced the coefficient of variation of synaptic currents in a model involving 250 receptors. This calls into question the use of variance measures for distinguishing pre- vs. postsynaptic sites of potentiation.

Although sometimes disputed, it has been assumed for several decades that new proteins synthesized following a learning event are required for consolidation of subsequent memory. Published findings and new results described here challenge this idea. Protein synthesis inhibitors did not prevent Theta Bust Stimulation (TBS) from producing extremely stable long-term potentiation (LTP) in experiments using standard hippocampal slice protocols. However, the inhibitors were effective under conditions that likely depleted protein levels prior to attempts to induce the potentiation effect. Experiments showed that induction of LTP at one input, and thus a prior episode of protein synthesis, eliminated the effects of inhibitors on potentiation of a second input even in depleted slices. These observations suggest that a primary role of translation and transcription processes initiated by learning events is to prepare neurons to support future learning. Other work has provided support for an alternative theory of consolidation. Specifically, if the synaptic changes that support memory are to endure, learning events/TBS must engage a complex set of signaling processes that reorganize and re-stabilize the spine actin cytoskeleton. This is accomplished in fast (10 min) and slow (50 min) stages with the first requiring integrin activation and the second a recovery of integrin functioning. These results align with, and provide mechanisms for, the long-held view that memories are established and consolidated over a set of temporally distinct phases.