Current Molecular Medicine - Volume 2, Issue 7, 2002

A great deal of research has been directed toward understanding the cellular mechanisms underlying synaptic plasticity and memory formation. To this point, most research has focused on the more “active” components of synaptic transmission: presynaptic transmitter release and postsynaptic transmitter receptors. Little work has been done characterizing the role neurotransmitter transporters might play during changes in synaptic efficacy. We review several new experiments that demonstrate glutamate transporters are regulated during changes in the efficacy of glutamatergic synapses. This regulation occurred during long-term facilitation of the sensorimotor synapse of Aplysia and long-term potentiation of the Schaffer-collateral synapse of the rat. We propose that glutamate transporters are “co-regulated” with other molecules / processes involved in synaptic plasticity, and that this process is phylogenetically conserved. These new findings indicate that glutamate transporters most likely play a more active role in neurotransmission than previously believed.

Our current understanding of the mechanisms of information processing and storage in the brain, based on the concept proposed more than fifty years ago by D. Hebb, is that a key role is played by changes in synaptic efficacy induced by coincident pre- and postsynaptic activity. Decades of studies of the properties of long-term potentiation (LTP) have shown that this form of plasticity adequately fulfills these requirements and is likely to contribute to several models of learning and memory. Recent analyses of the molecular events implicated in LTP are consistent with the view that modifications of receptor properties or insertion of new receptors account for the potentiation of synaptic transmission. These experiments, however, have also uncovered an unexpected structural plasticity of synapses. Dendritic spines appear to be dynamic structures that can be formed, modified in their shape or eliminated under the influence of activity. Furthermore, recent studies suggest that LTP, in addition to changes in synaptic function, is also associated with mechanisms of synaptogenesis. We review here the evidence pointing to this activity-dependent remodeling and discuss the possible role of this structural plasticity for synaptic potentiation, learning and memory.

There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections between neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular and molecular bases of learning and memory. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. Here we briefly review these mechanisms and illustrate with a few examples of animal models of neurological disorders how new knowledge about these mechanisms can provide valuable insights into identifying the mechanisms that go awry when memory is deficient, and how, in turn, characterisation of the dysfunctional mechanisms offers prospects to design and evaluate molecular and biobehavioural strategies for therapeutic prevention and rescue.

A large body of evidence has established a link between stressful life events and development or exacerbation of depression. At the cellular level, evidence has emerged indicating neuronal atrophy and cell loss in response to stress and in depression. At the molecular level, it has been suggested that these cellular deficiencies, mostly detected in the hippocampus, result from a decrease in the expression of brain-derived neurotrophic factor (BDNF) associated with elevation of glucocorticoids. Thus, an increase in expression of BDNF, facilitating both neuronal survival and neurogenesis, is thought to represent a converging mechanism of action of various types of antidepressant treatments (e.g., antidepressant drugs and transcranial magnetic stimulation). However, as also revealed by converging lines of evidence, high levels of glucocorticoids down-regulate hippocampal synaptic connectivity (‘negative’ metaplasticity), whereas an increase in expression of BDNF up-regulates connectivity in the hippocampus (‘positive’ metaplasticity). Therefore, antidepressant treatments might not only restore cell density but also regulate higher-order synaptic plasticity in the hippocampus by abolishing ‘negative’ metaplasticity, and thus restore hippocampal cognitive processes that are altered by stress and in depressed patients. This antidepressant regulatory effect on hippocampal synaptic plasticity function, which may, in turn, suppress ‘negative’ metaplasticity in other limbic structures, is discussed.

The prefrontal cortex is critical to working memory processes. Current theories of prefrontal function are largely based on primate behavioural and electrophysiological data. As molecular genetic techniques advance in mice, so investigations into the rodent prefrontal cortex should expand, such that rodent models of prefrontal function during working memory may be used to study the synaptic and molecular basis of the phenomenon. This review attempts to summarize aspects of published data that pertain to working memory and suggest directions that will allow a coherent comparison of prefrontal function and interaction in monkey, rat and mouse.

The striatum has long been known to be involved in the control of motor behavior, since disruption of dopamine-mediated function in this brain structure is directly linked to Parkinson's disease and other disorders of movement. However, it is now accepted that both dorsal and ventral striatal nuclei are also essential for a variety of cognitive processes, which depend on reward-based stimulus-response learning. Since the neuroanatomical and neurochemical organization of dorsal and ventral striatum is only partially overlapping, it is likely that both common and nucleus-specific cellular and molecular events contribute to synaptic plasticity, learning and memory processes mediated by these cerebral structures. Alterations in cell signaling in the striatum may be particularly important in the response to both acute and chronic administration of drugs of abuse, resulting in maladaptive changes in the reward-based associative learning involved in addiction, withdrawal and relapse.

Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and / or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.