Leptin and its role in hippocampal synaptic plasticity

It is well documented that the hormone leptin plays a pivotal role in regulating food intake and body weight via its hypothalamic actions. However, leptin receptors are expressed throughout the brain with high levels found in the hippocampus. Evidence is accumulating that leptin has widespread actions on CNS function and in particular learning and memory. Recent studies have demonstrated that leptin-deficient or-insensitive rodents have impairments in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze. Moreover, direct administration of leptin into the brain facilitates hippocampal long-term potentiation (LTP), and improves memory performance in mice. There is also evidence that, at the cellular level, leptin has the capacity to convert hippocampal short-term potentiation (STP) into LTP, via enhancing NMDA receptor function. Recent data indicates that leptin can also induce a novel form of NMDA receptor-dependent hippocampal long-term depression. Here, we review the evidence implicating a key role for the hormone leptin in modulating hippocampal synaptic plasticity and discuss the role of lipid signaling cascades in this process.     

A fresh look at the role of CaMKII in hippocampal synaptic plasticity and memory

Advances in molecular, genetic, and cell biological techniques have allowed neuroscientists to delve into the cellular machinery of learning and memory. The calcium and calmodulin-dependent kinase type II (CaMKII) is one of the best candidates for being a molecular component of the learning and memory machinery in the mammalian brain. It is present in abundance at synapses and its enzymatic properties and responsiveness to intracellular Ca(2+) fit a model whereby Ca(2+) currents activate the kinase and lead to changes in synaptic efficacy. Indeed, such plastic properties of synapses are thought to be important for memory formation. Genetic analysis of the alpha isoform of CaMKII in mice support the hypothesis that CaMKII signaling is required to initiate the formation of new spatial memories in the hippocampus. CaMKII is also required for the correct induction of long-term potentiation (LTP) in the hippocampus, consistent with the widely held belief that LTP is a mechanism for learning and memory. Recent cell biological, genetic, and physiological analyses suggest that one of the cellular explanations for LTP and CaMKII function might be the trafficking of AMPA-type receptors to synapses in response to neural activity.     

The role of cell adhesion molecules in synaptic plasticity and memory.

Studies in the past few years suggest that cell adhesion molecules may play signaling as well as structural roles at adult synapses during plasticity. The observation that many adhesion molecules are expressed both pre-synaptically and post-synaptically raises the possibility that information about synaptic activity might simultaneously be communicated to both sides of the synapse, circumventing the need for distinct anterograde and retrograde messengers.     

The role of synaptic ion channels in synaptic plasticity

The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory.     

Long-term synaptic plasticity in hippocampal interneurons

Rapid memory formation relies, at least in part, on long-term potentiation (LTP) of excitatory synapses. Inhibitory interneurons of the hippocampus, which are essential for information processing, have recently been found to exhibit not one, but two forms of LTP. One form resembles LTP that occurs in pyramidal neurons, which depends on N-methyl-D-aspartate receptors and is triggered by coincident pre- and postsynaptic activity. The other depends on Ca2+ influx through glutamate receptors that preferentially open when the postsynaptic neuron is at rest. Here we review these contrasting forms of LTP and describe how they are mirrored by two forms of long-term depression. We further discuss how the remarkable plasticity of glutamatergic synapses on interneurons greatly enhances the computational capacity of the cortical microcircuit.     

Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGL^AG-NH₂, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.     

Molecular and cellular cognitive studies of the role of synaptic plasticity in memory

Synaptic plasticity has a central role in nearly all models of learning and memory. Besides experiments documenting changes in synaptic function during learning, most of the evidence supporting a role for synaptic plasticity in memory comes from manipulations that either enhance or lesion synaptic processes. In the last decade, mouse transgenetics (knock outs and transgenics) have provided compelling evidence that the molecular mechanisms responsible for the induction and stability of synaptic changes have a critical role in the acquisition and storage of information. Here, I will review this literature, with a special focus on studies of hippocampal-dependent learning and memory.     

Modulation of hippocampal plasticity in learning and memory

Synaptic plasticity plays a central role in the study of neural mechanisms of learning and memory. Plasticity rules are not invariant over time but are under neuromodulatory control, enabling behavioral states to influence memory formation. Neuromodulation controls synaptic plasticity at network level by directing information flow, at circuit level through changes in excitation/inhibition balance, and at synaptic level through modulation of intracellular signaling cascades. Although most research has focused on modulation of principal neurons, recent progress has uncovered important roles for interneurons in not only routing information, but also setting conditions for synaptic plasticity. Moreover, astrocytes have been shown to both gate and mediate plasticity. These additional mechanisms must be considered for a comprehensive mechanistic understanding of learning and memory.     

Protein kinase signaling in synaptic plasticity and memory

The relay of extracellular signals into changes in cellular physiology involves a Byzantine array of intracellular signaling pathways, of which cytoplasmic protein kinases are a crucial component. In the nervous system, a great deal of effort has focused on understanding the conversion of patterns of synaptic activity into long-lasting changes in synaptic efficacy that are thought to underlie memory. The goal is both to understand synaptic plasticity mechanisms, such as long-term potentiation, at a molecular level and to understand the relationship of these synaptic mechanisms to behavioral memory. Although both involve the activation of multiple signaling pathways, recent studies are beginning to define discrete roles and mechanisms for individual kinases in the different temporal phases of both synaptic and behavioral plasticity.     

Mitogen-activated protein kinases in synaptic plasticity and memory

This review highlights five areas of recent discovery concerning the role of extracellular-signal regulated kinases (ERKs) in the hippocampus. First, ERKs have recently been directly implicated in human learning through studies of a human mental retardation syndrome. Second, new models are being formulated for how ERKs contribute to molecular information processing in dendrites. Third, a role of ERKs in stabilizing structural changes in dendritic spines has been defined. Fourth, a crucial role for ERKs in regulating local dendritic protein synthesis is emerging. Fifth, the importance of ERK interactions with scaffolding and structural proteins at the synapse is increasingly apparent. These topics are discussed within the context of an emerging role for ERKs in a wide variety of forms of synaptic plasticity and memory formation in the behaving animal.     

Protease‐activated receptor‐1 modulates hippocampal memory formation and synaptic plasticity

Protease‐activated receptor‐1 (PAR1) is an unusual G‐protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. Although previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. Here, we used PAR1?/? mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1?/? mice have deficits in hippocampus‐dependent memory. We also show that while PAR1?/? mice have normal baseline synaptic transmission at Schaffer collateral‐CA1 synapses, they exhibit severe deficits in N‐methyl‐d ‐aspartate receptor (NMDAR)‐dependent long‐term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR‐mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR‐dependent processes subserving memory formation and synaptic plasticity.     

Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation

The ERK/MAP kinase cascade is important for long-term memory formation and synaptic plasticity, with a myriad of upstream signals converging upon ERK activation. Despite this convergence of signaling, neurons routinely activate appropriate biological responses to different stimuli. Scaffolding proteins represent a mechanism to achieve compartmentalization of signaling and the appropriate targeting of ERK-dependent processes. We report that kinase suppressor of Ras (KSR1) functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Specificity of KSR1-dependent signaling also extends to specific downstream targets of ERK. Behaviorally and physiologically, we found that the absence of KSR1 leads to deficits in associative learning and theta burst stimulation-induced LTP. Our report provides novel insight into the endogenous scaffolding role of KSR1 in controlling kinase activation within the nervous system.     

Dynamics of memory representations in networks with novelty-facilitated synaptic plasticity

The ability to associate some stimuli while differentiating between others is an essential characteristic of biological memory. Theoretical models identify memories as attractors of neural network activity, with learning based on Hebb-like synaptic modifications. Our analysis shows that when network inputs are correlated, this mechanism results in overassociations, even up to several memories "merging" into one. To counteract this tendency, we introduce a learning mechanism that involves novelty-facilitated modifications, accentuating synaptic changes proportionally to the difference between network input and stored memories. This mechanism introduces a dependency of synaptic modifications on previously acquired memories, enabling a wide spectrum of memory associations, ranging from absolute discrimination to complete merging. The model predicts that memory representations should be sensitive to learning order, consistent with recent psychophysical studies of face recognition and electrophysiological experiments on hippocampal place cells. The proposed mechanism is compatible with a recent biological model of novelty-facilitated learning in hippocampal circuitry.     

The role of myosin V in exocytosis and synaptic plasticity

In neuroscience, myosin V motor proteins have attracted attention since they are highly expressed in brain, and absence of myosin Va in man leads to a severe neurological disease called Griscelli syndrome. While in some cells myosin V is described to act as a vesicle transport motor, an additional role in exocytosis has emerged recently. In neurons, myosin V has been linked to exocytosis of secretory vesicles and recycling endosomes. Through these functions, it is implied in regulating important brain functions including the release of neuropeptides by exocytosis of large dense-core vesicles and the insertion of neurotransmitter receptors into post-synaptic membranes. This review focuses on the role of myosin V in (i) axonal transport and stimulated exocytosis of large dense-core vesicles to regulate the secretion of neuroactive substances, (ii) tethering of the endoplasmic reticulum at cerebellar synapses to permit long-term depression, (iii) recycling of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors at hippocampal synapses during long-term potentiation, and (iv) recycling of nicotinic acetylcholine receptors at the neuromuscular junction. Myosin V is thus discussed as an important modulator of synaptic plasticity.     

The role of cluster receptor state in synaptic plasticity

Common postsynaptic mechanisms underlying formation and increase in efficiency of glutamate and GABA synapses are discussed. Much attention is given to clusterization of different receptor types as a mechanism of long-term potentiation. A possibility of synchronization of activities of receptors forming the same cluster is discussed.     

Proteomic analysis of activity-dependent synaptic plasticity in hippocampal neurons

Following long-term treatment with bicuculline and tetrodotoxin (TTX) aimed at modifying synaptic activity in cultured neurons, we used a proteomic approach to identify the associated changes in protein expression. The neurons were left untreated, or treated with bicuculline or TTX, and fractionated by means of differential detergent extraction, after which the proteins in each fraction were separated by means of two-dimensional (2D) gel electrophoresis, and 57 proteins of interest were identified by mass spectrometry. The proteins that showed altered expression and/or post-translational modifications include proteins or enzymes involved in regulating cell and protein metabolism, the cytoskeleton, or mitochondrial activity. These results suggest that extensive alterations in neuronal protein expression take place as a result of increased or decreased synaptic activity.     

Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity

The peripheral functions of hormones such as leptin, insulin and estrogens are well documented. An important and rapidly expanding field is demonstrating that as well as their peripheral actions, these hormones play an important role in modulating synaptic function and structure within the CNS. The hippocampus is a major mediator of spatial learning and memory and is also an area highly susceptible to epileptic seizure. As such, the hippocampus has been extensively studied with particular regard to synaptic plasticity, a process thought to be necessary for learning and memory. Modulators of hippocampal function are therefore of particular interest, not only as potential modulators of learning and memory processes, but also with regard to CNS driven diseases such as epilepsy. Hormones traditionally thought of as only having peripheral roles are now increasingly being shown to have an important role in modulating synaptic plasticity and dendritic morphology. Here we review recent findings demonstrating that a number of hormones are capable of modulating both these phenomena.Key words: synaptic plasticity, leptin, estrogen, insulin, hippocampus, LTD, LTP     

Molecular mechanisms of synaptic plasticity and memory.

To unravel the molecular and cellular bases of learning and memory is one of the most ambitious goals of modern science. The progress of recent years has not only brought us closer to understanding the molecular mechanisms underlying stable, long-lasting changes in synaptic strength, but it has also provided further evidence that these mechanisms are required for memory formation.