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     

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.     

Electron microscopic 3D-reconstruction of dendritic spines in cultured hippocampal neurons undergoing synaptic plasticity

Dendritic spines are assumed to constitute the locus of neuronal plasticity, and considerable effort has been focused on attempts to demonstrate that new memories are associated with the formation of new spines. However, few studies that have documented the appearance of spines after exposure to plasticity-producing paradigms could demonstrate that a new spine is touched by a bona fida presynaptic terminal. Thus, the functional significance of plastic dendritic spine changes is not clearly understood. We have used quantitative time lapse confocal imaging of cultured hippocampal neurons before and after their exposure to a conditioning medium which activates synaptic NMDA receptors. Following the experiment the cultures were prepared for 3D electron microscopic reconstruction of visually identified dendritic spines. We found that a majority of new, 1- to 2-h-old spines was touched by presynaptic terminals. Furthermore, when spines disappeared, the parent dendrites were sometime touched by a presynaptic bouton at the site where the previously identified spine had been located. We conclude that new spines are most likely to be functional and that pruned spines can be transformed into shaft synapses and thus maintain their functionality within the neuronal network.     

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.     

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.     

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.     

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.     

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.     

Mitochondrial regulation of synaptic plasticity in the hippocampus

Synaptic mechanisms of plasticity are calcium-dependent processes that are affected by dysfunction of mitochondrial calcium buffering. Recently, we observed that mice deficient in mitochondrial voltage-dependent anion channels, the outer component of the mitochondrial permeability transition pore, have impairments in learning and hippocampal synaptic plasticity, suggesting that the mitochondrial permeability transition pore is involved in hippocampal synaptic plasticity. In this study, we examined the effect on synaptic transmission and plasticity of blocking the permeability transition pore with low doses of cyclosporin A and found a deficit in synaptic plasticity and an increase in base-line synaptic transmission. Calcium imaging of presynaptic terminals revealed a transient increase in the resting calcium concentration immediately upon incubation with cyclosporin A that correlated with the changes in synaptic transmission and plasticity. The effect of cyclosporin A on presynaptic calcium was abolished when mitochondria were depolarized prior to cyclosporin A exposure, and the effects of cyclosporin A and mitochondrial depolarization on presynaptic resting calcium were similar, suggesting a mitochondrial locus of action of cyclosporin A. To further characterize the calcium dynamics of the mitochondrial permeability transition pore, we used an in vitro assay of calcium handling by isolated brain mitochondria. Cyclosporin A-exposed mitochondria buffered calcium more rapidly and subsequently triggered a more rapid mitochondrial depolarization. Similarly, mitochondria lacking the voltage-dependent anion channel 1 isoform depolarized more readily than littermate controls. The data suggest a role for the mitochondrial permeability transition pore and voltage-dependent anion channels in mitochondrial synaptic calcium buffering and in hippocampal synaptic plasticity.     

Hotheaded: TRPV1 as mediator of hippocampal synaptic plasticity

TRPV1 is a sensory transduction channel that mediates thermal nociception and some aspects of pathological pain. In this issue of Neuron, Gibson et al. report that TRPV1 also plays important roles in hippocampal synaptic plasticity, presenting a potential challenge for TRPV1-targeted therapeutics for the treatment of pain.     

Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice

Collybistin (Cb) is a brain-specific guanine nucleotide exchange factor that has been implicated in plasma membrane targeting of the postsynaptic scaffolding protein gephyrin found at glycinergic and GABAergic synapses. Here we show that Cb-deficient mice display a region-specific loss of postsynaptic gephyrin and GABA(A) receptor clusters in the hippocampus and the basolateral amygdala. Cb deficiency is accompanied by significant changes in hippocampal synaptic plasticity, due to reduced dendritic GABAergic inhibition. Long-term potentiation is enhanced, and long-term depression reduced, in Cb-deficient hippocampal slices. Consistent with the anatomical and electrophysiological findings, the animals show increased levels of anxiety and impaired spatial learning. Together, our data indicate that Cb is essential for gephyrin-dependent clustering of a specific set of GABA(A) receptors, but not required for glycine receptor postsynaptic localization.     

Biochemical mechanisms for translational regulation in synaptic plasticity

Changes in gene expression are required for long-lasting synaptic plasticity and long-term memory in both invertebrates and vertebrates. Regulation of local protein synthesis allows synapses to control synaptic strength independently of messenger RNA synthesis in the cell body. Recent reports indicate that several biochemical signalling cascades couple neurotransmitter and neurotrophin receptors to translational regulatory factors in protein synthesis-dependent forms of synaptic plasticity and memory. In this review, we highlight these translational regulatory mechanisms and the signalling pathways that govern the expression of synaptic plasticity in response to specific types of neuronal stimulation.