AMPA receptor modulators as cognitive enhancers

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Abstract

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors mediate fast excitatory transmission throughout the central nervous system. Positive modulation of these receptors can potentially enhance cognition by, firstly, offsetting losses of glutamatergic synapses; secondly, promoting synaptic plasticity; and thirdly, increasing the production of trophic factors. The advent of small molecules that selectively enhance AMPA receptors in the brain made it possible to test these hypotheses. Preclinical experiments indicate that the compounds accelerate the encoding of memory and have positive effects on models of cognitive dysfunction. Initial results with human subjects are also positive. AMPA receptor modulators thus represent an entirely new approach to cognitive enhancement and the treatment of diverse brain disorders.

Section snippets

Introduction: rationale for the development of AMPA receptor modulators as cognitive enhancers

Identification of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptor as the postsynaptic mediator of fast excitatory transmission in the brain constitutes one of the major achievements of contemporary neuroscience. Efforts to exploit this information in the development of pharmaceuticals have, until recently, centered on blocking degenerative events attendant to excessive concentrations of the transmitter glutamate, as occurs during injury or ischemia.

Categories of positive modulators

AMPA receptors are heteromeric complexes composed of four subunits, each of which has a binding pocket for the transmitter glutamate. Recent work with site-directed mutagenesis and x-ray crystallography has gone a long way towards explaining how the receptors gate synaptic current and desensitize in the continued presence of transmittter [3••]. Transmitter binding changes the linkage between the extracellular domains and the transmembrane pore of the receptor. This perturbation opens the

Effects on brain physiology, networks and neurotrophins

Positive modulators penetrate the brain and increase monosynaptic responses in the cortical telencephalon 6., 20.. Particularly impressive results are described for a biarylpropylsulfonamide, which doubled the probability of cell spiking recorded in the prefrontal cortex 80 ms after stimulation of the ventral subiculum [21]. Given this delay, it can be assumed that the measured responses reflect polysynaptic effects; this is important because slice experiments have shown that ampakines have

Memory and cognition

Ampakines enhance the encoding of memory in a variety of animal models (Table 1). Short-term (minutes) memory scores were reliably increased in well-trained rats performing a delayed non-match to sample problem [34]. Detailed behavioral analyses traced the improvement to a reduction in proactive interference, a phenomenon that occurs when performance on preceding trials hinders encoding of information on subsequent trials. In support of the selective nature of the memory-enhancing effect,

Clinical results

Clinical results with AMPA receptor modulators are limited. An initial study used healthy 65–75 year old individuals and found improvements in the free (unprompted) recall of nonsense syllables. Tests were conducted under conditions in which baseline memory operations should be at least normal; that is, the subjects were rested, familiar with the procedures, and examined when alert and engaged. Recall in the highest ampakine dose group was more than twofold greater than for individuals given

Conclusions

Positive modulators facilitate excitatory transmission and network level activity in the cortical telencephalon. Their effects are surprisingly selective, given that they have the potential of affecting the large majority of synapses in the brain. Plausible explanations for this have been developed but are largely untested. The modulators promote the induction of LTP, potently enhance memory across an impressive array of paradigms, and appear to be effective in animal models of psychiatric

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

The author thanks BE Willman-Kozimor and LL Colgin for their assistance in preparation of this manuscript.

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