2004, Number 4
Understanding the neurobiological mechanisms of learning and memory: cellular, molecular and gene regulation implicated in synaptic plasticity and long-term potentiation. Part IV C
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ABSTRACTExtensive cellular and behavioral studies have led to the postulation that memories are encoded by changes in synaptic strength between neurons, as demonstrated by the correlation between the long-term changes in animal’s behavior and longterm changes in neuronal connections underlying a specific behavior in invertebrate animals, or even in vertebrate animals, where cellular models of synaptic plasticity using genetic approaches, such as Long-Term Potentiation (LTP) and Long-Term Depression (LTD), have been shown to depend on long-term changes in synaptic activity implicated in behavioral learning and memory. Long-term memory (LTM) is crucial for animal’s survival and represents a mechanism that underlies fundamental neurobiological events in the Nervous System of vertebrate and non-vertebrate species including the human. Long-term changes in synaptic connectivity as well as long-term behavioral changes (both activities that underlie several properties of LTM and are used as a parameter to explain the long-lasting enhancement of neuronal function after a stimulus) have been demonstrated to rely on signals that initially occur in the cell body. LTP is a form of synaptic plasticity widely accepted as a cellular model for stabilization of synapses in neurobiological phenomena, such as development and learning and memory. Much of the experimental work concerning LTP in learning has been focused on the NMDA receptor-dependent forms of LTP. But several questions have arisen regarding the issue if LTP equals memory. If LTP has a real role in memory, a more appropriate hypothesis should be stated by postulating that activity-dependent synaptic plasticity and multiple forms of memory known to exist, share a common core; that is, the synaptic plasticity and memory hypothesis states that activity dependent synaptic plasticity is induced at appropriate synapses during memory formation. Synaptic plasticity is a physiological phenomenon that induces specific patterns of neural activity sustained by chemical and molecular mechanisms, that give rise to changes in synaptic efficacy and neural excitability that long outlast the events that trigger them. Based on the several properties of synaptic plasticity discovered, LTP may be proposed as a suitable neuronal mechanism for the development of several memory systems, including initial encoding and storage of memory traces and initial phases of trace consolidation over time. Such memory processing made up by LTP or LTD most probably occur as a network specific process, making LTP a universal mechanism for encoding and storting memory traces and what gets encoded is part of a network property rather than mechanisms working at individual synapses. For example, the type of information processed at the hippocampus is quite different from the information processed by the amygdala, and such information should remain if the mechanisms of plasticity operating in each brain area are conserved. Decades of research have demonstrated that LTP in the hippocampus is induced by synaptic activity and that cytoplasmic membrane-bound molecule(s) are required to transduce extracellular signals mediated by receptor-activation into activation of intracellular signaling processes. Most of these processes depend on intracellular calcium activity, and thereby on calcium-dependent mechanisms that are recruited for LTP induction and expression. For instance, NMDA receptors have been shown to be essential for initiation of LTP, but expression of this phenomenon in brought primarily by AMPA receptors. Induction of LTP in CA1 hippocampal region has been shown to depend on increases of intracellular calcium and activation of specific calcium-dependent molecules, such as the calcium/calmodulin-dependent protein kinase (CaMKII), whose cell expression is confined predominantly at postsynaptic densities. Moreover, long-term expression of LTP requires protein synthesis, where transient signals will be linked to activation of specific genes that ultimately will determine growth and remodeling of potential active synapses. Different types of synapses may express and use a different set of molecules mediating activation of intracellular signaling pathways for initiating and maintaining synaptic plasticity. Several studies have demonstrated that neuronal modifications of neurotransmitter receptors or membrane-receptor subunits at postsynaptic densities represent one of the neuronal mechanisms by which neurons regulate their synaptic strength. For instance, it has been demonstrated that neuronal dendrites are able to regulate their own transmembrane receptor synthesis in response to external stimuli (i.e., GluR2 subunit of AMPA receptor) and such molecular mechanisms pose important implications in the understanding of how individual synapses are selectively strengthened. In addition, recent experiments have demonstrated that specific intracellular signaling molecules (i.e., neuronal Synaptic GTPase-activating protein or SynGAP) is selectively expressed and enriched at excitatory synapses. Interesting enough, are the evidences that demostrate that different subsets of protein kinases (MAPKs, SAPKs, MAPKAKs, p38MAPK, etc.) and intracellular signaling pathways activate transcription factors (AP-1 complex, CREB) that regulate the expression of different immediate early genes (IEG) that are crucial for neuronal development, glutamate receptor trafficking to specific synapses and for LTP induction. Much of the neurochemical and molecular changes that occurred in synaptic plasticity, may be well associated with dynamic morphological changes in spine synapses as suggested to participate in the development and consolidation of LTP. In addition, glial cells, known to participate in the excitatory neurotransmission in the CNS besides their conceptualized cellular function, as elements for structural support and homeostasis; may play an important role in synaptic plasticity and thereby may regulate the information processed in the brain. As hippocampal LTP, has been the target of intensive molecular genetic analysis, several studies have demonstrated that LTP is altered when particular single genes are knocked out or overexpressed in null mutant mice or transgenic mice. Such studies have led to the amazing observation that variations in LTP exist within natural inbred mouse strains.
CAMMAROTA M, BEVILAQUA LR, ARDENGHI P, PARATCHA G, LEVI DE STEIN M et al.: Learningassociated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: abolition by NMDA receptor blockade. Brain Res Mol Brain Res, 76(1):36-46, 2000.