The role of protein phosphatase-1 in the modulation of synaptic and structural plasticity

Synaptic plasticity is a phenomenon contributing to changes in the efficacy of neuronal transmission. These changes are widely believed to be a major cellular basis for learning and memory. Protein phosphorylation is a key biochemical process involved in synaptic plasticity that operates through a tight balance between the action of protein kinases and protein phosphatases (PPs). Although the majority of research in this field has concentrated primarily on protein kinases, the significant role of PPs is becoming increasingly apparent. This review examines one such phosphatase, PP1, and highlights recent advances in the understanding of its intervention in synaptic and structural plasticity and the mechanisms of learning and memory.     

Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals

Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity, and it influences synaptic plasticity. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling.     

Presence of adrenocorticotropin and β-Endorphin immunoreactivities in the magnocellular neurosecretory system of the rat hypothalamus

Summary Antisera raised against ACTH (1–39), -endorphin and the 16K proopiocortin were used, in association with the immunoperoxidase reaction, to localize positively-staining cell bodies and nerve fibres in the hypothalamus of the rat. Antigens, cross-reactive against anti-ACTH (1–39) serum were detected in a fibre system in the rostro-dorsal hypothalamus situated between the optic chiasm and the third ventricle while immunoreactive 16K-like material was present in fibres localized in the caudal hypothalamus, dorso-lateral to the arcuate nucleus. This latter system was also associated with the appearance of ACTH (1–39) and ACTH (17–39) immunoreactivity.Cells of the arcuate nucleus stained positively for ACTH (1–39), 16K antigen and -endorphin, and on examining adjacent thin sections it was observed that cells that contained 16K antigen-like material, also gave a positive immunoreaction with ACTH (1–39) and -endorphin antisera. In the magnocellular system, cells of the supraoptic (SON) and paraventricular (PVN) nuclei also gave a positive immunoreaction with anti-ACTH (1–39), 16K antigen and -endorphin serum. As in the case of the arcuate nucleus, common cells stained for these three antigens.On the basis of the precursor theory for the synthesis of ACTH, 16K antigen and -endorphin, it was not unexpected to find these three fragments of pro-opiocortin localized together in cells of the arcuate nucleus. That ACTH (1–39), 16K antigen and -endorphin-like materials are present in the magnocellular neurosecretory system would suggest that cells of the SON and PVN are not only involved in the synthesis of neurophysin and the neurohypophysial hormones, but also of some products of the pro-opiocortin molecule. Whether the biochemical nature of the ACTH and -endorphin in cells of the SON and PVN is identical to that of anterior pituitary origin remains to be established, as does the biosynthetic relationship between neurophysin and oxytocin/ vasopressin and these fragments of pro-opiocortin.Drs. M.M. Wilkes, S.S.C. Yen, G. Pelletier, B.A. Eipper and R. Walter are thanked for supplying some of the antisera and antigens used in this study. Thanks also go to Ciba-Geigy Ltd. and Organon Inc. for supplies of ACTH (17–39) and ACTH (1–24) respectively. This work was financed by The Medical Research Council of New Zealand     

Expression pattern of Zac1 mouse gene, a new zinc-finger protein that regulates apoptosis and cellular cycle arrest, in both adult brain and along development

Using in situ hybridization, we analyzed the expression pattern of the Zac1 gene in mouse brain during the embryonic and postnatal development. Zac1 is a new gene that regulates extensive apoptosis and cell cycle arrest through unrelated pathways. At embryonic stages, strong expression was observed in brain areas with active proliferation (ventricular zone and numerous neuroepithelius) and in nervous system (neural retina and neural tube). In addition, some areas with differentiation activity were noticeably labeled such as arcuate nucleus and amygdaloid region of the brain together with other embryonic sites (hindlimb, forelimb and somites). From P0 onwards, the expression appeared in some proliferative areas, such as subventricular zone and cerebellum (external granular layer and Purkinje cells) and in some synaptic plasticity areas, such as the dorso and ventromedial hypothalamic nuclei, arcuate nucleus, ventral thalamic nucleus.     

Synaptosomal non-mitochondrial ATPase activities and drug treatment

Energy-using non-mitochondrial ATPases were assayed in rat cerebral cortex synaptosomes and synaptosomal subfractions, namely synaptosomal plasma membranes and synaptic vesicles. The following enzyme activities were evaluated: Na⁺, K⁺-ATPase; high- and low-affinity Ca²⁺-ATPase; basal Mg²⁺-ATPase; Ca²⁺, Mg²⁺-ATPase. The evaluations were performed after four week-treatment with saline [controls] or -adrenergic agents (-yohimbine, clonidine), energymetabolism interfering compound (theniloxazine), and oxygen-partial pressure increasing agent (almitrine), in order to define the plasticity and the selective changes in individual ATPases. In rat cerebral cortex, the enzyme adaptation to four-week-treatment with -yohimbine or clonidine was characterized by increase in both high- and low-affinity Ca²⁺-ATPase activities. The action involves the enzyme form located in the synaptic plasma membranes. The enzyme adaptation to the subchronic treatments with theniloxazine or almitrine was characterized by increase in Na⁺, K⁺-ATPase or Mg²⁺-ATPase activities, respectively. The action involves the enzymatic forms located in the synaptic plasma membranes. Thus, the pharmacodynamic effects of the agents tested should also be related to the changes induced in the activity of some specific synaptosomal nonmitochondrial ATPases.     

Chelation of hippocampal zinc enhances long‐term potentiation and synaptic tagging/capture in CA1 pyramidal neurons of aged rats: implications to aging and memory

Aging is associated with decline in cognitive functions, prominently in the memory consolidation and association capabilities. Hippocampus plays a crucial role in the formation and maintenance of long‐term associative memories, and a significant body of evidence shows that impairments in hippocampal function correlate with aging‐related memory loss. A number of studies have implicated alterations in hippocampal synaptic plasticity, such as long‐term potentiation (LTP), in age‐related cognitive decline although exact mechanisms underlying are not completely clear. Zinc deficiency and the resultant adverse effects on cognition have been well studied. However, the role of excess of zinc in synaptic plasticity, especially in aging, is not addressed well. Here, we have investigated the hippocampal zinc levels and the impairments in synaptic plasticity, such as LTP and synaptic tagging and capture (STC), in the CA1 region of acute hippocampal slices from 82‐ to 84‐week‐old male Wistar rats. We report increased zinc levels in the hippocampus of aged rats and also deficits in the tetani‐induced and dopaminergic agonist‐induced late‐LTP and STC. The observed deficits in synaptic plasticity were restored upon chelation of zinc using a cell‐permeable chelator. These data suggest that functional plasticity and associativity can be successfully established in aged neural networks by chelating zinc with cell‐permeable chelating agents.     

Failed Stabilization for Long-Term Potentiation in the Auditory Cortex of Fmr1 Knockout Mice

Fragile X syndrome is a developmental disorder that affects sensory systems. A null mutation of the Fragile X Mental Retardation protein 1 (Fmr1) gene in mice has varied effects on developmental plasticity in different sensory systems, including normal barrel cortical plasticity, altered ocular dominance plasticity and grossly impaired auditory frequency map plasticity. The mutation also has different effects on long-term synaptic plasticity in somatosensory and visual cortical neurons, providing insights on how it may differentially affect the sensory systems. Here we present evidence that long-term potentiation (LTP) is impaired in the developing auditory cortex of the Fmr1 knockout (KO) mice. This impairment of synaptic plasticity is consistent with impaired frequency map plasticity in the Fmr1 KO mouse. Together, these results suggest a potential role of LTP in sensory map plasticity during early sensory development.     

Deep brain stimulation

During the last decade deep brain stimulation (DBS) has become a routine method for the treatment of advanced Parkinsons disease (PD), leading to striking improvements in motor function and quality of life of PD patients. It is associated with minimal morbidity. The rationale of targeting specific structures within basal ganglia such as the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is strongly supported by the current knowledge of the basal ganglia pathophysiology, which is derived from extensive experimental work and which provides the theoretical basis for surgical therapy in PD. In particular, the STN has advanced to the worldwide most used target for DBS in the treatment of PD, due to the marked improvement of all cardinal symptoms of the disease. Moreover on-period dyskinesias are reduced in parallel with a marked reduction of the equivalent daily levodopa dose following STN–DBS. The success of the therapy largely depends on the selection of the appropriate candidate patients and on the precise implantation of the stimulation electrode, which necessitates careful imaging-based pre-targeting and extensive electrophysiological exploration of the target area. Despite the clinical success of the therapy, the fundamental mechanisms of high-frequency stimulation are still not fully elucidated. There is a large amount of evidence from experimental and clinical data that stimulation frequency represents a key factor with respect to clinical effect of DBS. Interestingly, high-frequency stimulation mimics the functional effects of ablation in various brain structures. The main hypotheses for the mechanism of high-frequency stimulation are: (1) depolarization blocking of neuronal transmission through inactivation of voltage dependent ion-channels, (2) jamming of information by imposing an efferent stimulation-driven high-frequency pattern, (3) synaptic inhibition by stimulation of inhibitory afferents to the target nucleus, (4) synaptic failure by stimulation-induced neurotransmitter depletion. As the hyperactivity of the STN is considered a functional hallmark of PD and as there is experimental evidence for STN-mediated glutamatergic excitotoxicity on neurons of the substantia nigra pars compacta (SNc), STN–DBS might reduce glutamatergic drive, leading to neuroprotection. Further studies will be needed to elucidate if STN–DBS indeed provides a slow-down of disease progression.     

大鼠丘脑侧后核到初级视皮层突触传递的短时程可塑性

大鼠丘脑侧后核(lateral posterior thalamic nucleus,LP nucleus)到初级视皮层的突触连接是膝体外视觉通路的重要组成部分.运用场电位记录和电泳的方法在位研究了该视觉回路突触传递的短时程可塑性.结果表明,无论是运用双脉冲刺激还是串刺激都能观察到明显的短时程抑制特性.电泳荷包牡丹碱(bicuculline)和2-hydroxy-saclofen使该抑制作用减弱,电泳钙离子使抑制加强,电泳APV对抑制作用没有明显影响.所以突触前递质释放水平的改变,和γ-氨基丁酸(GABA)能受体（尤其是GABA_B受体）的活动都会影响该回路突触传递的短时程可塑性,而N-甲基-D-天冬氨酸(NMDA)受体则几乎没有作用.该回路很强的短时程抑制特性可能与LP核在视觉注意中的作用有关.     

Steroid-induced developmental plasticity in hypothalamic astrocytes: implications for synaptic patterning.

We have previously demonstrated that astrocytes in the developing arcuate nucleus of the rat hypothalamus exhibit a sexually dimorphic morphology as a result of differential exposure to gonadal steroids. Testosterone via its aromatized byproduct, estrogen, induces arcuate astrocytes to undergo differentiation during the first few days of life. These differentiated astrocytes exhibit a stellate morphology. Coincident with the steroid-induced increase in astrocyte differentiation is a reduction of dendritic spines on arcuate neurons. As a result, the arcuate nucleus of males has fewer axodendritic spine synapses than females and this dimorphism is retained throughout life. In the immediately adjacent ventromedial nucleus, neonatal astrocytes are immature and unresponsive to steroids. Neurons in this region show no change in dendritic spines in the first few days of life but do exhibit increased dendritic branching as a result of testosterone exposure. These findings illustrate the importance of distinct populations of astrocytes in restricted brain regions and their potential importance to the establishment of regionally specific synaptic patterning. Conflicting reports leave the site of steroid-mediated astrocyte responsiveness in the arcuate nucleus unresolved: Are gonadal steroids acting directly on astrocytes or are steroid-concentrating neurons mediating astrocytic responsiveness? In this review, we discuss the current understanding of astrocyte-neuron interactions and the possible mechanisms for steroid-mediated, astrocyte-directed synaptic patterning in the developing hypothalamus.     

On the structure of the human striate area. Lamina IVcβ

Summary Layer IVc of the human striate area consists mainly of a great number of small spinous local circuit neurons which store numerous characteristic lipofuscin granules. Since the neurons of the neighbouring layers are almost devoid of pigment deposits the boundaries of lamina IVc are easily traceable. Hence, the pigment granules can be used as internal markers to unequivocally identify these small pigmented spinous local circuit neurons of lamina IVc in ultrathin sections. They have a large spherical nucleus surrounded by a narrow cytoplasmic rim poor in organelles, and very scarcely receive axosomatic symmetric synapses.Within layer IVc four types of synaptic boutons can be distinguished. Type-1-boutons are large, contain a few and loosely arranged round vesicles and make asymmetric synaptic contacts with dendrites and dendritic spines. The type-2-boutons which are also large are filled with densely packed round vesicles which accumulate at the presynaptic membrane. The large type-3-boutons are characterized by elongated vesicles and symmetric synaptic contact zones. These boutons generate several fingerlike protrusions. Small profiles which contain elongated vesicles and form symmetric synaptic contacts, are most probably parts of these protrusions. The large amount of small boutons with round vesicles and asymmetric synaptic contact zones are tentatively described as type-4-boutons although it is far from certain that they represent a uniform class. The presumable origins of the different types of boutons are discussed.Supported by the Deutsche Forschungsgemeinschaft (Br. 634/1)Dedicated to Prof. Dr. med. H. Leonhardt in honor of his 60th birthday     

The VirD2 protein of Agrobacterlum tumefaciens carries nuclear localization signals important for transfer of T-DNA to plants

Agrobacterium tumefaciens is able to transfer a piece of DNA, the T-DNA, to the nucleus of the plant cell. The VirD2 protein is required for the production of the T-DNA, it is tightly linked to the T-DNA and it is thought to direct it to the plant genome. Two nuclear localization signals (NLS), one in the N-terminal part and one in the C-terminal part of the VirD2 protein, have been shown to be able to target marker proteins to the plant nucleus. Here we analyze nuclear entry of the T-DNA complex using a new and very sensitive assay for T-DNA transfer. We show that optimal T-DNA transfer requires the VirD2 NLS located in the C-terminal part of the protein, whereas mutations in the N-terminal NLS coding sequence seem to have no effect on T-DNA transfer.     

Rules of engagement: factors that regulate activity-dependent synaptic plasticity during neural network development

Overproduction and pruning during development is a phenomenon that can be observed in the number of organisms in a population, the number of cells in many tissue types, and even the number of synapses on individual neurons. The sculpting of synaptic connections in the brain of a developing organism is guided by its personal experience, which on a neural level translates to specific patterns of activity. Activity-dependent plasticity at glutamatergic synapses is an integral part of neuronal network formation and maturation in developing vertebrate and invertebrate brains. As development of the rodent forebrain transitions away from an over-proliferative state, synaptic plasticity undergoes modification. Late developmental changes in synaptic plasticity signal the establishment of a more stable network and relate to pronounced perceptual and cognitive abilities. In large part, activation of glutamate-sensitive N-methyl-d-aspartate (NMDA) receptors regulates synaptic stabilization during development and is a necessary step in memory formation processes that occur in the forebrain. A developmental change in the subunits that compose NMDA receptors coincides with developmental modifications in synaptic plasticity and cognition, and thus much research in this area focuses on NMDA receptor composition. We propose that there are additional, equally important developmental processes that influence synaptic plasticity, including mechanisms that are upstream (factors that influence NMDA receptors) and downstream (intracellular processes regulated by NMDA receptors) from NMDA receptor activation. The goal of this review is to summarize what is known and what is not well understood about developmental changes in functional plasticity at glutamatergic synapses, and in the end, attempt to relate these changes to maturation of neural networks.     

Bidirectional plasticity gated by hyperpolarization controls the gain of postsynaptic firing responses at central vestibular nerve synapses

Linking synaptic plasticity with behavioral learning requires understanding how synaptic efficacy influences postsynaptic firing in neurons whose role in behavior is understood. Here, we examine plasticity at a candidate site of motor learning: vestibular nerve synapses onto neurons that mediate reflexive movements. Pairing nerve activity with changes in postsynaptic voltage induced bidirectional synaptic plasticity in vestibular nucleus projection neurons: long-term potentiation relied on calcium-permeable AMPA receptors and postsynaptic hyperpolarization, whereas long-term depression relied on NMDA receptors and postsynaptic depolarization. Remarkably, both forms of plasticity uniformly scaled synaptic currents evoked by pulse trains, and these changes in synaptic efficacy were translated into linear increases or decreases in postsynaptic firing responses. Synapses onto local inhibitory neurons were also plastic but expressed only long-term depression. Bidirectional, linear gain control of vestibular nerve synapses onto projection neurons provides a plausible mechanism for motor learning underlying adaptation of vestibular reflexes.     

Developmental changes in the brain-stem serotonergic nuclei of teleost fish and neural plasticity

Summary 1. During early ontogeny, the serotonergic neurons in the brain stem of the three-spined stickleback shows a temporal and spatial developmental pattern that closely resembles that of amniotes.2. However, in the adult fish, only the midline nuclei of the rostral group (dorsal and median raphe nuclei) and the dorsal lateral tegmental nucleus are consistently serotonin-immunoreactive (5-HTir), whereas the groups of the upper and lower rhombencephalon (raphe pontis, raphe magnus, and raphe pallidus/obscurus nuclei) are variable and, when present, contain relatively small numbers of 5-HTir neurons.3. Using specific antisera against tryptophan 5-hydroxylase and aromaticl-amino acid decarboxylase, we have shown that the lateral B9 group and the groups of the upper and lower rhombencephalon are consistently present in adult sticklebacks. The results are discussed in relation to other known instances of neurotransmitter plasticity or transient neurotransmitter expression in teleost fish.4. While there are several instances of transient expression of neurotransmitter markers by discrete neuronal populations, there is so far no evidence of changes from one neurotransmitter phenotype to another in the brain of teleost fish. However, there are indications of plasticity of expression of catecholamines and indoleamines, and their respective synthesizing enzymes, as reflected in age-dependent changes and variation between individuals of different physiological status.5. As the brain grows continuously in teleost fish, and new neurons are added from proliferative regions, synaptic connections may be expected to undergo remodeling in all brain regions throughout life. Thus, the teleostean brain may be considered a suitable model for experimental studies of different aspects of neural plasticity.     

Competitive anatomical and physiological plasticity: a neurotrophic bridge

Understanding the mechanisms of competitive synaptic plasticity, both anatomical and physiological, is of central importance to developmental neuroscience. Neurotrophic factors (NTFs) are implicated at almost every level of synaptic plasticity, from rapid physiological effects to slower anatomical effects, in addition to being implicated in competitive plasticity. Previously, we have built and analysed a mathematical model of anatomical synaptic plasticity based on competition for neurotrophic support. Here, we extend our work to build a combined, anatomical and physiological model. We find that, in order to understand the mechanisms of competitive physiological plasticity, we must postulate a central role for the change in expression of NTF receptors (NTFRs) on afferent synaptic terminals. Only by supposing that the expression of NTFRs is governed by NTF uptake do we find that physiological plasticity is competitive in character. We perform a fixed point analysis that establishes when afferent segregation is possible as a function of the parameters in the model, and simulate the model numerically to shed further light on its properties. A very clear prediction emerges from our model: that, as the efficacy of a terminal that is destined to be retracted due to competitive interactions reduces to zero, the NTFRs on that terminal should be down-regulated. Furthermore, our model requires that this reduction in synaptic efficacy never occurs significantly before the down-regulation in NTFRs. Such a prediction should be testable, and renders our model capable of being invalidated, in contrast to many other models of synaptic competition, which merely impose rather than seek to illuminate the quintessential feature of developmental synaptic plasticity. Received: 14 May 1999 / Accepted in revised form: 29 November 1999     

Influences of different developmental periods of taurine supplements on synaptic plasticity in hippocampal CA1 area of rats following prenatal and perinatal lead exposure

Background  

Previous study has demonstrated that dietary taurine supplement protected rats from impairments of synaptic plasticity induced by postnatal lead exposure. However, little is known about the role of taurine in the presence of prenatal and perinatal lead exposure. We investigated the possible effect of taurine supplement on prenatal and perinatal lead-induced synaptic plasticity deficit and determined developmental periods critical for the effect of taurine.