NCBI Bookshelf A service of the National Library of Medicine National Institutes of Health Siegel GJ Agranoff BW Albers RW et al editors Basic Neurochemistry Molecular Cellular and Medical Aspects 6th edition Philadelphia Lippincott Raven 1999 Studies of Learning and Memory in Vertebrates Bernard W Agranoff Carl W Cotman and Michael D Uhler Correspondence to Bernard W Agranoff Mental Health Research Institute University of Michigan 1103 E Huron Ann Arbor Michigan 48104 1687 Rodents particularly the mouse and rat have been by far the most favored experimental vertebrate animals for behavioral study The mouse is appropriate for genetic studies because of the availability of inbred populations including many mutant strains and for available transgenic techniques for manipulation of genomic sequences The rabbit has been useful for studies on classical conditioning employing the eye blink response The avian brain has proven attractive for the study of behavioral imprinting in which newborn chicks and ducklings follow a moving object to which they are first exposed following hatching Neurochemical correlates such as increased macromolecular synthesis have been investigated extensively 23 Changes in macromolecular synthesis in the roof of the avian telencephalon have been correlated with successful imprinting of a taste aversion Acquisition of birdsong has been associated with immediate early gene encoding in the forebrain of zebra finches and canaries Lower primates are of special interest because of the similarity in their CNS structure to that of the human The concept that higher brain function can be localized receives support from studies on human learning and memory employing PET and fMRI see below Long term potentiation leads to structural changes at the synapse Learning and memory formation are thought to involve structural changes in the brain specifically at the synapses but the mechanisms underlying these processes remain elusive One of the goals of neuroscience research has been to identify and understand these synaptic correlates of mammalian learning and memory As previously discussed learning involves an adaptive change in response to a stimulus In the mammalian brain LTP is a useful synaptic correlate of learning and memory 24 As a function of an increase in the frequency of action potentials or of stimulus history some pre synaptic pathways can generate a long lasting potentiation in the magnitude of the synaptic potential After a series of short high frequency synaptic bursts 100 per second the amplitude of the synaptic response increases and can be maintained in vivo at the increased level for days or weeks LTP is particularly robust in higher cortical structures such as the hippocampus Detailed studies have shown that development of LTP requires a stimulus threshold determined by complex interactions between the frequency and the strength of the electrical stimulation to the afferent pathway This requirement correlates with both a release of neurotransmitter from the presynaptic cells and a strong depolarization of the postsynaptic cells LTP can be elicited in vitro see below It should be noted however that LTP has not been clearly associated with any behavioral modification observed in an intact animal As shown in Figure 50 5 the anatomical arrangement of synaptic connections within the hippocampus renders this structure particularly amenable to experiment Furthermore these pathways are preserved in a hippocampal slice a section of the hippocampus which can be experimentally studied for many hours Three distinct classes of hippocampal synaptic connections have been studied the perforant path consists of axons from the entorhinal cortex that synapse with granule cells of the dentate gyrus axons designated as mossy fibers of these dentate granule cells in turn synapse with pyramidal cells of the CA3 region and the CA3 pyramidal cells synapse with CA1 neurons and form the Schaffer collateral pathway Although each of these three pathways may develop LTP the mossy fiber pathway to CA3 neurons is unique in several ways The Schaffer collateral pathway is the most widely studied and best understood of these synaptic pathways Figure 50 5 Diagram of the hippocampal network of neurons involved in long term potentiation LTP Neurons of the entorhinal cortex innervate the dentate granule cells which send mossy fiber tracts to the pyramidal cells of the CA3 region which more One of the most impressive aspects of LTP is synapse specificity For example although a given CA1 neuron may receive many afferent synapses from distinct CA3 pyramidal cells LTP generally will be observed only in the synapses of afferents that have received the tetanic stimulation There is considerable evidence to indicate that glutamate plays a key role as the excitatory neurotransmitter in LTP formation 25 Since antagonists of the N methyl D aspartate NMDA receptor such as 4 amino 5 phosphonovaleric acid see Chap 17 can prevent induction of LTP it has been proposed that postsynaptic receptors activated during LTP are of the NMDA type This is true for LTP observed in both the dentate and CA1 neurons The metabotropic glutamate receptor mG1uR plays a key role in induction of LTP whether or not NMDA receptors are additionally activated When stimulation conditions are optimal for LTP formation there appears to be a significant increase in postsynaptic Ca2 This Ca2 increase is required for LTP in CA1 neurons since injection of EGTA and other Ca2 chelating agents into postsynaptic neurons prevents LTP It remains uncertain precisely how the elevation of post synaptic Ca2 leads to LTP The most strongly favored hypotheses involve Ca2 activation of one or more protein kinases but the identity of these kinases is unclear PKC activation has been shown to occur following induction of LTP and this activation is required for LTP formation as determined by studies of mice deficient in PKC 25 It has even been postulated that phosphorylation of GAP 43 by PKC may be required PKC is activated by Ca2 as well as by diacylglycerol DAG released in the breakdown of the phosphoinositides see Chap 21 A second protein kinase implicated in LTP is Ca2 calmodulin dependent protein kinase II CaMKII which may constitute up to 20 of the protein in postsynaptic density preparations When activated by Ca2 CaMKII is autophosphorylated This prolongs its activity in the absence of Ca2 Many of the in vitro properties of this enzyme can be
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