Trends in Neurosciences
OpinionAmpakines and the threefold path to cognitive enhancement
Introduction
AMPA-type glutamate receptors mediate fast excitatory postsynaptic currents (EPSCs) at the great majority of brain synapses and are widely regarded as an expression mechanism for the memory-related long-term potentiation (LTP) effect. Compounds that freely cross the blood–brain barrier and have sufficient potency to modulate these receptors positively (i.e. ampakines) were first introduced in 1993–1994 1, 2. Ampakines bind to a site on the AMPA receptor but have no agonist or antagonist effects; instead, they stabilize the receptor in its channel-open state following the binding of released transmitter (glutamate). This prolongs current flow through the receptor and thus enhances synaptic responses. Given that excessive glutamate-mediated activity is a cause of seizures and excitotoxic brain damage 3, 4, it was anticipated that positive modulators of AMPA receptors would produce unacceptable side-effects. Unexpectedly, the early ampakines did not cause such effects at doses that both increased excitatory transmission in the hippocampus and noticeably altered behavior. These initial findings were followed by a series of animal studies showing that the drugs accelerate learning 2, 5, 6, 7, reduce age-related memory impairments [8], and suppress symptoms in models of schizophrenia 9, 10, 11, attention-deficit hyperactivity disorder (ADHD) [12] and depression 13, 14. A much more limited body of studies in humans, most using mild versions of ampakines, has found positive effects on memory in the elderly [15] and in psychiatric diseases [16]. Ampakines thus have the potential to act as broad-spectrum therapeutic agents for psychiatric disorders.
Neurobiological studies have identified three routes by which ampakines affect disturbed behavior.
- (i)
Deficits in transmission strength within the cortex probably contribute to the cognitive impairments associated with aging [17] and various neuropsychiatric diseases 18, 19; ampakines enhance transmission, without causing noticeable side-effects, and therefore are plausible treatments for such conditions [19].
- (ii)
Ampakines, through established mechanisms, both lower the induction threshold and increase the magnitude of LTP [20]. Given the links between LTP and memory 21, 22, 23, these results explain why the drugs accelerate learning.
- (iii)
Ampakines enhance the trophic effects of excitatory transmission. Production of brain-derived neurotrophic factor (BDNF) and related proteins is regulated by excitatory input 24, 25 and, consonant with this, their concentrations in the brain are increased by ampakines 26, 27, 28, 29, 30. BDNF exerts potent, acute effects on synaptic plasticity 31, 32, 33, and thus could mediate various behavioral effects associated with ampakines.
Although these three pathways explain the broad effects of ampakines on neuropsychiatric disturbances, it is noteworthy that each one is fully operative in normal brains. This raises the questions of whether ampakines will positively affect intact, in addition to compromised, behaviors, and whether such effects would extend to cognition. Pertinent to these issues, ampakines improved retention scores in complex tasks performed by animals 2, 5, 34, 35 or humans [36]. For example, monkeys required to select a complex target object out of a field of six similar objects had much better scores when tested under the influence of an ampakine [35] and these positive effects became more pronounced as task complexity was increased. Ampakines have also been reported to improve learning of a difficult visuospatial maze by young adult humans [36]. The effects in this instance were not nearly as dramatic as those recorded for rats and monkeys, but this could be because much lower drug concentrations were used in the human studies.
Although these observations indicate that ampakines act as cognition enhancers, they do not specify mechanisms (how does an increase in BDNF affect a particular cognitive activity?) and they are not predictive (which aspects of cognition will be affected?). Missing from the discussion is any consideration of how the drugs affect cortical networks – those structures that lie between the synaptic AMPA receptors targeted by the drugs and observable behavior. Here we will (i) argue that each of the three pathways of ampakine action will produce a characteristic modification to network operations, and (ii) discuss how these effects will both alter and enhance cognition.
Section snippets
Effects of ampakines on glutamate receptors and synaptic transmission
The original ampakines were benzamide compounds that with further synthesis and testing evolved into two subgroups 1, 2. Subsequent work by different groups resulted in three additional, chemically distinct families of small molecule (300–500 Da) modulators: pyridothiadiazines [37], biarylpropylsulfonamides [38] and 5′-alkyl-benzothiadiazides [39]. Compounds from each of these groups, all of which are referred to here as ampakines, have positive effects in animal models of learning [40],
The first path to cognitive enhancement: increase transmission to expand cortical networks
Repeated assembly (and disassembly) of complex functional networks, which are largely composed of glutamatergic neurons, is the only explanation so far advanced for how the cortex carries out the computations that underlie cognition. Limits on the size of such networks, and thus on the complexity of cognitive operations, can reasonably be assumed to reflect the reliability of transmission at individual synapses. According to this argument, the nonlinearities built into the generation of a
The second path: facilitate LTP to accelerate learning
The NMDA-type glutamate receptors that trigger LTP are normally voltage blocked and depend on depolarization produced by the colocalized AMPA receptors for activation. Because the pertinent channels are relatively slow to open, this dependency extends to both the duration and the amplitude of the AMPA receptor-mediated currents. According to a recent report [54], ampakine variants that only increase response amplitude (deactivation drugs, as already mentioned) simply lower the threshold for
The third path: upregulate BDNF to improve memory consolidation
Multiple lines of work indicate that the excitatory inputs to cortical neurons regulate the expression of BDNF and nerve growth factor (NGF) 61, 62. Consonant with this, ampakines induce BDNF expression in vitro and in vivo 27, 28, 42 and do so without causing evident disturbances to ongoing behavior. BDNF applied to slices potently facilitates the induction of LTP 32, 63 and experiments using selective antagonists indicate that endogenous BDNF, which is released by the theta-burst stimulation
Concluding remarks
Ampakines have large effects on polysynaptic EPSCs and selectively increase aggregate cortical activity associated with complex tasks in rats and monkeys. This accords with the idea that the drugs provide a means for obviating the limits on network size that are imposed by probabilistic transmission failures. The expectation that this would lead to new cognitive capacities remains to be formally tested. As expected from their positive effects on LTP, ampakines accelerate learning across diverse
Acknowledgements
Research supported, in part, by grants NS0518237 and NS45260 from NINDS.
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