Reelin, lipoprotein receptors and synaptic plasticity

Apolipoprotein E (APOE) is a cholesterol transport protein and an isoform-specific major risk factor for neurodegenerative diseases. The lipoprotein receptors that bind APOE have recently been recognized as pivotal components of the neuronal signalling machinery. The interaction between APOE receptors and one of their ligands, reelin, allows them to function directly as signal transduction receptors at the plasma membrane to control not only neuronal positioning during brain development, but also synaptic plasticity in the adult brain. Here, we review the molecular mechanisms through which APOE, cholesterol, reelin and APOE receptors control synaptic functions that are essential for cognition, learning, memory, behaviour and neuronal survival.     

MPTP modulates hippocampal synaptic transmission and activity-dependent synaptic plasticity via dopamine receptors

Parkinson's disease (PD)-like symptoms and cognitive deficits are inducible by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Since cognitive abilities, including memory formations rely also on hippocampus, we set out to clarify the effects of MPTP on hippocampal physiology. We show that bath-application of MPTP (25?μM) to acute hippocampal slices enhanced AMPA receptor-mediated field excitatory postsynaptic potentials (AMPAr-fEPSPs) transiently, whereas N-methyl-D-aspartate (NMDA) receptor-mediated fEPSPs (NMDAr-fEPSPs) were facilitated persistently. The MPTP-mediated transient AMPAr-fEPSP facilitation was antagonized by the dopamine D2-like receptor antagonists, eticlopride (1?μM) and sulpiride (1 and 40?μM). In contrast, the persistent enhancement of NMDAr-fEPSPs was prevented by the dopamine D1-like receptor antagonist SCH23390 (10?μM). In addition, we show that MPTP decreased paired-pulse facilitation of fEPSPs and mEPSCs frequency. Regarding activity-dependent synaptic plasticity, 25?μM MPTP transformed short-term potentiation (STP) into a long-term potentiation (LTP) and caused a slow onset potentiation of a non-tetanized synaptic input after induction of LTP in a second synaptic input. This heterosynaptic slow onset potentiation required activation of dopamine D1-like and NMDA-receptors. We conclude that acute MPTP application affects basal synaptic transmission by modulation of presynaptic vesicle release and facilitates NMDAr-fEPSPs as well as activity-dependent homo- and heterosynaptic plasticity under participation of dopamine receptors.     

Estrogen and hippocampal synaptic plasticity

During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system,including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.     

ApoE isoform-dependent changes in hippocampal synaptic function

Accumulating evidence suggests that neurons prone to degeneration in Alzheimer's Disease (AD) exhibit evidence of re-entry into an aberrant mitotic cell cycle. Our laboratory recently demonstrated that, in a genomic amyloid precursor protein (APP) mouse model of AD (R1.40), neuronal cell cycle events (CCEs) occur in the absence of beta-amyloid (Aβ) deposition and are still dependent upon the amyloidogenic processing of the amyloid precursor protein (APP). These data suggested that soluble Aβ species might play a direct role in the induction of neuronal CCEs. Here, we show that exposure of non-transgenic primary cortical neurons to Aβ oligomers, but not monomers or fibrils, results in the retraction of neuronal processes, and induction of CCEs in a concentration dependent manner. Retraction of neuronal processes correlated with the induction of CCEs and the Aβ monomer or Aβ fibrils showed only minimal effects. In addition, we provide evidence that induction of neuronal CCEs are autonomous to primary neurons cultured from the R1.40 mice. Finally, our results also demonstrate that Aβ oligomer treated neurons exhibit elevated levels of activated Akt and mTOR (mammalian Target Of Rapamycin) and that PI3K, Akt or mTOR inhibitors blocked Aβ oligomer-induced neuronal CCEs. Taken together, these results demonstrate that Aβ oligomer-based induction of neuronal CCEs involve the PI3K-Akt-mTOR pathway.     

Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity.

During development, Eph receptors mediate the repulsive axon guidance function of ephrins, a family of membrane attached ligands with their own receptor-like signaling potential. In cultured glutamatergic neurons, EphB2 receptors were recently shown to associate with NMDA receptors at synaptic sites and were suggested to play a role in synaptogenesis. Here we show that Eph receptor stimulation in cultured neurons modulates signaling pathways implicated in synaptic plasticity, suggesting cross-talk with NMDA receptor-activated pathways. Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity. In EphB2(-/-) hippocampal slices, protein synthesis-dependent long-term potentiation (LTP) was impaired, and two forms of synaptic depression were completely extinguished. Interestingly, targeted expression of a carboxy-terminally truncated form of EphB2 rescued the EphB2 null phenotype, indicating that EphB2 kinase signaling is not required for these EphB2-mediated functions.     

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.     

A molecular biological approach to synaptic plasticity and learning

Until the more recent advances made in molecular biology, attempts to link synaptic plasticity and learning have focused on using LTP as a marker of learning-induced synaptic plasticity, where one has expected to observe the same magnitude of change in synaptic strength as that observed with artificial stimulation. To a large extent this approach has been frustrated by the fact that it is generally assumed that the representation of the memory traces is distributed thoughout widespread networks of cells. By implication it is more likely that one would observe small distributed changes within a network; a formidable task to measure. In this review we describe how the advances in molecular biology give us both the tools to investigate the mechanisms of synaptic plasticity and to apply these to investigations of the underlying mechanisms in learning and the formation of memories that have until now remained out of our grasp.     

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.     

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     

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.     

Steroid-induced hippocampal synaptic plasticity: sex differences and similarities

Early in development, steroid hormones structurally organize various regions of the CNS. However, steroid hormones continue to affect the structure and function of the CNS throughout the life of the individual. In this review, we discuss sex differences and similarities in steroid-induced synaptic plasticity in the adult brain. Particular emphasis is placed on steroid-induced plasticity in the hippocampus, a brain region important in learning and memory. This topic is relevant to the growing evidence for the actions of sex hormones outside of the reproductive neuroendocrine axis. It also tells an important and emerging story about non-genomic and genomic actions of steroids at the cellular and molecular levels. Specifically, the effects of estrogen and progesterone as well as the androgens and glucocorticoids are discussed. The influence of steroids on hippocampal structure and function can differ vastly between the sexes. However, there are certain similarities that might aid in our understanding of how steroids affect CNS plasticity in general. Although future studies will undoubtedly lead us to a greater understanding of these phenomena, the data reviewed indicate that when studying synaptic plasticity, the sex and hormonal milieu of the individual might significantly influence the outcome and interpretation of the research.     

Eph-ephrin与突触可塑性

Eph受体酪氨酸激酶及其配体ephrin广泛参与神经系统的发育,如轴突导向、细胞迁移、体节形成和血管生成。最近研究显示的Ephephrin在突触的定位提示其与突触可塑性有关。Ephephrin对成年神经系统的可塑性、学习和记忆,以及神经损伤后的再生可能具有重要的调节作用。     

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.     

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.     

Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity

Cholinergic modulation of hippocampal synaptic plasticity has been studied extensively by applying receptor agonists or blockers; however, the effect of rapid physiological cholinergic stimuli on plasticity is largely unknown. Here, we report that septal cholinergic input, activated either by electrical stimulation or via an optogenetic approach, induced different types of hippocampal Schaffer collateral (SC) to CA1 synaptic plasticity, depending on the timing of cholinergic input relative to the SC input. When the cholinergic input was activated 100 or 10 ms prior to SC stimulation, it resulted in α7 nAChR-dependent long-term potentiation (LTP) or short-term depression, respectively. When the cholinergic stimulation was delayed until 10 ms after the SC stimulation, a muscarinic AChR-dependent LTP was induced. Moreover, these various forms of plasticity were disrupted by Aβ exposure. These results have revealed the remarkable temporal precision of cholinergic functions, providing a novel mechanism for information processing in cholinergic-dependent higher cognitive functions.     

Regulatory mechanisms of AMPA receptors in synaptic plasticity

Activity-dependent changes in the strength of excitatory synapses are a cellular mechanism for the plasticity of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) are the main transducers of rapid excitatory transmission in the mammalian CNS, and recent discoveries indicate that the mechanisms which regulate AMPARs are more complex than previously thought. This review focuses on recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis. These relationships offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling.