NEUROTRANSMITTER SYSTEMS AND MEMORY

Ever since the discovery of the chemical nature of synaptic transmission, the role of neurotransmitters in the formation and retrieval of memories has been the subject of intense scientific investigation. As the number of both neurotransmitters and forms of memories has been steadily increasing over the years, the task of uncovering general principles describing the involvement of neurotransmitter systems in memory has become extremely difficult. Furthermore, the lack of understanding of the molecular and cellular mechanisms of learning and memory has limited the experimental approaches to two general strategies: (1) an interventional strategy using pharmacological tools or lesion/stimulation of specific neurotransmitter systems; and (2) a correlational strategy using "naturally" occurring conditions (neurological diseases, aging) affecting specific neurotransmitter systems, or genetically engineered mutant mice. Based on these studies, a number of neurotransmitters and neuronal pathways using these neurotransmitters have consistently demonstrated an important role in learning and memory (Chapoutier, 1989; Decker and McGaugh, 1991).

Glutamate

In early work using an avian retina preparation, proline was found to inhibit glutamate release; as pro-line had also been shown to inhibit learning and memory in chicks, researchers suggested that glutamate played a significant role in learning and memory. Building on these results, Cherkin and his colleagues (1976) published a series of articles demonstrating that various glutamate antagonists injected intracerebrally could retard memory consolidation in neonatal chicks, using a behavioral paradigm involving flavor aversion learning. In the 1990s, the role of glutamate in learning and memory received considerable support from two independent lines of research. First, the most studied cellular model of learning and memory is the long term potentiation (LTP) of synaptic transmission elicited by brief bursts of high-frequency electrical stimulation of monosynaptic pathways using glutamate as a neurotransmitter (Malenka and Nicoll, 1999). The relationships among LTP, learning and memory, and glutamatergic systems have been further established by the use of specific antagonists of different subtypes of glutamate receptors (Morris et al., 1990), which clearly established that LTP induction is due to NMDA receptor activation while LTP maintenance involves modification of AMPA receptors. Manipulations affecting either type of receptors were found to have significant effect on learning and memory processes. For instance, positive modulators of AMPA receptors, the ampakines, have been shown to be cognitive enhancers (Ingvar et al., 1997), indicating that up-regulation of AMPA receptor-mediated synaptic responses facilitate LTP formation and AMPA LTP-mediated learning and memory processes. Likewise, overexpression of one subunit of NMDA receptors in mice, the NR2B subunit, resulted in increased LTP and learning and memory (Tsien, 2000). Second, various human conditions associated with major disturbances of memory exhibit marked degeneration of glutamatergic neurons. Thus, severe cases of amnesia are the result of loss of glutamatergic neurons in the hippocampal formation (Squire, 1986), and one of the hallmarks of Alzheimer's disease is a loss of glutamatergic neurons in entorhinal cortex and hippocampus (Hyman et al., 1987). All these studies point out to the critical role of glutamatergic pathways of the hippocampus in the formation of long-term memories.

GABA (γ-Aminobutyric Acid)

Historically, GABAergic neurons have been neglected as possible participants in memory processes. The discovery of the mode of action of benzodiazepines and the known effects of these compounds on memory renewed the interest in the possible role of GABA in memory. Thus benzodiazepines potentiate the effect of GABA at the GABA_A receptors and generally produce an impairment of learning, whereas ligands acting at the benzodiazepine sites but producing an opposite effect (and therefore called reverse agonists) enhance learning in mice, chickens, and humans (Lister, 1985). Local administration of GABA agonists or antagonists in discrete brain regions have been effective in producing impairment or enhancement, respectively, in various learning tasks (McGaugh, 1989). In this case as well, the links between the GABAergic systems and LTP have been proposed to account for the role of GABA in learning and memory, as inhibition of GABA receptors generally facilitate LTP induction, while potentiation of GABA receptors prevent LTP induction.

Acetylcholine

Acetylcholine has long been involved in learning and memory (Deutsch, 1983). Pharmacological studies using both acetylcholinesterase inhibitors (producing increased levels of acetylcholine at synapses) and blockers of acetylcholine receptors have been performed in numerous learning tasks and animal species. The general conclusion is that impairment of cholinergic transmission produces cognitive impairment. This conclusion is also reinforced by studies in humans with pathological alterations in cholinergic function. Thus, Alzheimer's disease is associated with loss of cholinergic neurons in the nucleus basalis of Meynert (Coyle et al., 1983). In Parkinson's disease, memory impairment is correlated with a decrease in cholinergic function in the frontal cortex (Chapoutier, 1989). A possible unifying mechanism for a role of cholinergic neurons in memory processes has been ascribed to the participation of these neurons in the generation of rhythmical brain activity (θ and γ rhythms) directly involved in information storage and in LTP (Winson, 1990). In particular, actylcholine-induced synchronization of neuronal firing in the theta range (5 to 7 hertz) produces optimal conditions for summation of excitatory depolarization, thereby facilitating activation of NMDA receptors, LTP induction, and ultimately memory formation.

Catecholamines, Serotonin, and Histamine

Although noradrenergic systems have often been implicated in learning and memory (Gold and Zornetser, 1983), studies using pharmacological blockade of norepinephrine receptors or destruction of noradrenergic neurons indicate that these neurons do not directly participate in the learning of a variety of tasks (Pontecorvo et al., 1988). However, the situation is probably more complicated, for noradrenergic, serotonergic, and histaminergic systems appear to participate in the modulation of some memory processes (D'Hooge and De Deyn, 2001). Depending on which subtype of receptors is activated under particular conditions, facilitation or inhibition or memory formation has been observed. In particular, it is now clear that spatial learning, which is often used to study mechanisms of learning and memory, depends upon the coordinated action of several brain regions and neurotransmitter systems. In addition, researchers have repeatedly argued that these modulatory systems are activated under numerous behavioral conditions (arousal and stress), which in turn affect information processing and storage in sensory and associational pathways.

Other Systems

Although not generally considered as neurotransmitters, a growing number of peptides have been found to be colocalized with traditional neurotransmitters and have been assigned the role of neuromodulators. Their role in synaptic function is still a matter of debate, but it is impossible not to mention the evidence implicating a number of neuropeptides in memory processes. In particular, ACTH and fragments of ACTH have repeatedly been shown to improve memory consolidation. Vasopressin has also been suggested as participating in memory formation, possibly through an interaction with noradrenergic systems (D'Hooge and De Deyn, 2001). Similarly, opioid peptides have been clearly implicated in memory processes, including the suggestion (Gallagher, 1985) that opioid peptide-containing neurons are part of a forgetting mechanism. Much attention has been devoted to the role of the steroid hormone estrogen in memory formation, as estrogen replacement therapy was found to alleviate cognitive deficits in postmenopausal women. The recent discovery that estrogen potentiates AMPA and NMDA receptor function and facilitates LTP induction provides a bridge between the cellular effects of estrogen and its behavioral effects. This finding also raises interesting questions related to the evolution of memory systems and of their relationships to reproductive and sexual behaviors.

Conclusion

As it becomes more and more widely accepted that learning and memory reflect the existence of a variety of synaptic plasticity mechanisms occurring at numerous stages of information processing and in different neuronal networks participating in information storage, it is not surprising that several neurotransmitter systems participate, directly or indirectly, in the processes of information storage and retrieval. The initial notion that one neurotransmitter was involved in one form of behavior has long been dismissed in favor of the idea that distributed and parallel neuronal networks participate in multiple sensory, motor, and cognitive operations. While the roles of glutamate and glutamatergic pathways as well as the functional significance of modifications of synaptic efficacy at glutamatergic synapses in this process are starting to be well established, leading to the development of the first "memory pill," the task of correlating the roles of other neurotransmitters and other neuronal pathways to specific forms of learning and memory still awaits the development of more specific pharmacological tools and behavioral tests. In particular, it is of crucial importance to define learning characteristics that are both species and time dependent as the demands on the learning and memory machinery are exquisitely sensitive to species requirements and time windows adapted to the particular species. It is clear, however, that this strategy will result in the development of more refined pharmacological treatments with potentials for alleviating more specific learning and memory disorders.

See also:COGNITIVE ENHANCERS; GLUTAMATE RECEPTORS AND THEIR CHARACTERIZATION

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MichelBaudry

Joel L.Davis