Neurotransmitters as ion shuttles in regulation of neural activity.

A molecular framework is described within which a single neural cell can modulate its excitability, or the quantity of transmitter released upon stimulation, in relationship to past stimulation. The key elements in this regulating system are complexation in the synaptic area by the transmitter molecule with extracellular ions, interaction of the complexed transmitter with the presynaptic receptor, possibly followed by reuptake of complexed transmitter.A number of mechanisms are suggested by which the transmitter/metal ion complex can regulate cellular function. Calculations are made to estimate the possible degree of change in the interior calcium concentration of a catecholaminergic cell by a calcium ion complex formed in the synapse. Experimental evidence is cited, which(a) documents the existence in the catecholaminergic cell of the necessary machinery for a calcium-ion-regulated cell-use registry device.(b) supports the hypothesis that catecholamines transport metal ions in neural systems, and(c) indicates that the ionic shuttle function of neurotransmitters plays a significant, but not exclusive, role in the transport of calcium. Calcium transported in this manner may be uniquely distinguishable from that derived from other sources of intracellular calcium in its temporal or spatial distribution. The existing evidence is discussed and rationalized with respect to the hypothesis that one of the chief presynaptic functions of many neurotransmitters is to feedback regulate cell function by performance as an ion shuttle.     

Preserved morphology and physiology of excitatory synapses in profilin1-deficient mice

Profilins are important regulators of actin dynamics and have been implicated in activity-dependent morphological changes of dendritic spines and synaptic plasticity. Recently, defective presynaptic excitability and neurotransmitter release of glutamatergic synapses were described for profilin2-deficient mice. Both dendritic spine morphology and synaptic plasticity were fully preserved in these mutants, bringing forward the hypothesis that profilin1 is mainly involved in postsynaptic mechanisms, complementary to the presynaptic role of profilin2. To test the hypothesis and to elucidate the synaptic function of profilin1, we here specifically deleted profilin1 in neurons of the adult forebrain by using conditional knockout mice on a CaMKII-cre-expressing background. Analysis of Golgi-stained hippocampal pyramidal cells and electron micrographs from the CA1 stratum radiatum revealed normal synapse density, spine morphology, and synapse ultrastructure in the absence of profilin1. Moreover, electrophysiological recordings showed that basal synaptic transmission, presynaptic physiology, as well as postsynaptic plasticity were unchanged in profilin1 mutants. Hence, loss of profilin1 had no adverse effects on the morphology and function of excitatory synapses. Our data are in agreement with two different scenarios: i) profilins are not relevant for actin regulation in postsynaptic structures, activity-dependent morphological changes of dendritic spines, and synaptic plasticity or ii) profilin1 and profilin2 have overlapping functions particularly in the postsynaptic compartment. Future analysis of double mutant mice will ultimately unravel whether profilins are relevant for dendritic spine morphology and synaptic plasticity.     

Acute injections of brain‐derived neurotrophic factor in a vocal premotor nucleus reversibly disrupt adult birdsong stability and trigger syllable deletion

Behavioral variability serves an essential role in motor learning by enabling sensory feedback to select those motor patterns that minimize error. Birds use auditory feedback to learn how to sing, and their songs lose variability and become highly stereotyped, or crystallized, at the end of a sensitive period for sensorimotor learning. The molecular cues that regulate song variability are not well understood. In other systems, neurotrophins, and brain‐derived neurotrophic factor (BDNF) in particular, can mediate various forms of neural plasticity, including sensitive period neural circuit plasticity and activity‐dependent synapse formation, and may also influence learning and memory. Here, we have tested the hypothesis that neurotrophin expression in the robust nucleus of the arcopallium (RA), the telencephalic output controlling song, regulates song variability. BDNF and its receptor trkB are expressed in RA, and BDNF expression in RA appears to be highest in juveniles, when song is most variable and plastic, and synapse density highest. Thus, song variability and synaptic connectivity could be enhanced by augmented expression of BDNF in RA. In support of this idea, we found that BDNF injections into the adult RA induced the re‐expression of juvenile‐like phenotypes, including song variability and an increased synaptic density in RA. Furthermore, BDNF treatment also induced vocal plasticity, characterized by syllable deletions and persistent changes to the song patterns. These results suggest that endogenous BDNF could be a molecular regulator of the song variability essential to vocal plasticity and, ultimately, to song learning. © 2004 Wiley Periodicals, Inc. J Neurobiol, 2005     

Imaging circuit formation in zebrafish

The study of nervous system development has been greatly facilitated by recent advances in molecular biology and imaging techniques. These approaches are perfectly suited to young transparent zebrafish where they have allowed direct observation of neural circuit assembly in vivo. In this review we will highlight a number of key studies that have applied optical and genetic techniques in zebrafish to address questions relating to axonal and dendritic arbor development,synapse assembly and neural plasticity. These studies have revealed novel cellular phenomena and modes of growth that may reflect general principles governing the assembly of neural circuits.     

Application of organization-activation theory to alternative male reproductive strategies: a review

Many species have extreme within-sex morphological and behavioral polymorphisms, most commonly different male phenotypes that practice different reproductive strategies. Although much is known about the role of hormones in sexual differentiation, little is known about what role hormones might play in within-sex differentiation. The relative plasticity hypothesis is derived from the classical organization-activation model of hormone action. It distinguishes between two types of polymorphic systems: a fixed system in which individual males assume one phenotype for their adult lives and a plastic system in which individual males can change phenotypes at least once. By analogy to sexual differentiation, the relative plasticity hypothesis generally predicts that organizational influences of hormones will be more important in fixed systems and activational influences of hormones will be more important in plastic systems. A review of our knowledge of the role of hormones in differentiation of within-sex polymorphisms indicates that the relative plasticity hypothesis accounts for otherwise diverse and contradictory results. This further supports the hypothesis that the organizational-activational model of hormone action derived from sexual differentiation generalizes to within-sex polymorphisms. However, studies of the effects of hormone manipulations on within-sex differentiation are rare but are desperately needed to further our understanding of this problem. Further studies of discontinuous behavioral variation characteristic of polymorphic species may further our understanding of the physiological basis of within-sex behavior variation in all species.     

Correlation between cardiac oxidative stress and myocardial pathology due to acute and chronic norepinephrine administration in rats

BACKGROUND: To investigate the cardiotoxic role of reactive oxygen species (ROS) and of products derived from catecholamines auto-oxidation, we studied: (1) the response of antioxidant cardiac cellular defence systems to oxidative stress induced by norepinephrine (NE) administration, (2) the effect of NE administration on cardiac beta1-adrenergic receptors by means of receptor binding assay, (3) the cellular morphological alterations related to the biologically cross-talk between the NE administration and cytokines [tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), interleukins IL6, IL8, IL10]. METHODS AND RESULTS: A total of 195 male rats was used in the experiment. All animals underwent electrocardiogram (EKG) before being sacrificed. The results obtained show that NE administration influences the antioxidant cellular defence system significantly increasing glutathione peroxidase (GPx) activity, glutathione reductase (GR) and superoxide dismutase (SOD). The oxidized glutathione (GSH/GSSG) ratio significantly decreases and malondialdehyde (MDA) levels increase showing a state of lipoperoxidation of cardiac tissue. We describe a significant apoptotic process randomly sparse in the damaged myocardium and the effect of ROS on the NE-mediated TNF-alpha, MCP-1, and IL6, IL8, IL10 production. CONCLUSIONS: Our results support the hypothesis that catecholamines may induce oxidative damage through reactive intermediates resulting from their auto-oxidation, irrespective of their interaction with adrenergic receptors, thus representing an important factor in the pathogenesis of catecholamines-induced cardiotoxicity. The rise of the cardioinhibitory cytokines may be interpreted as the adaptive response of jeopardized myocardium with respect to the cardiac dysfunction resulting from NE injection.     

New players tip the scales in the balance between excitatory and inhibitory synapses

Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.     

Targeting the Hippocampal Mossy Fiber Synapse for the Treatment of Psychiatric Disorders

It is widely known that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain. This neurogenesis has been implicated in depression and antidepressant treatments. Recent evidence also suggests that the dentate gyrus is involved in the neuropathology and pathophysiology of schizophrenia and other related psychiatric disorders. Especially, abnormal neuronal development in the dentate gyrus may be a plausible risk factor for the diseases. The synapse made by the mossy fiber, the output fiber of the dentate gyrus, plays a critical role in regulating neuronal activity in its target CA3 area. The mossy fiber synapse is characterized by remarkable activity-dependent short-term synaptic plasticity that is established during the postnatal development and is supposed to be central to the functional role of the mossy fiber. Any defects, including developmental abnormalities, in the dentate gyrus and drugs acting on the dentate gyrus can modulate the mossy fiber-CA3 synaptic transmission, which may eventually affect hippocampal functions. In this paper, I review recent evidence for involvement of the dentate gyrus and mossy fiber synapse in psychiatric disorders and discuss potential importance of drugs targeting the mossy fiber synapse either directly or indirectly in the therapeutic treatments of psychiatric disorders.     

Neuron-astrocyte signaling in the development and plasticity of neural circuits

Emerging evidence indicates that signaling between perisynaptic astrocytes and neurons at the tripartite synapse plays an important role during the critical period when neural circuits are formed and refined. Cross-talk between astrocytes and neurons during development mediates synaptogenesis, synapse elimination and structural plasticity through a variety of secreted and contact-dependent signals. Recent live imaging studies reveal a dynamic and cooperative interplay between astrocytes and neurons at synapses that is guided by a variety of molecular cues. A unifying theme from these recent findings is that astrocytes can promote the development and plasticity of synaptic circuits. Insight into the molecular mechanisms by which astrocytes regulate the wiring of the brain during development could lead to new therapeutic strategies to promote repair and rewiring of neural circuits in the mature brain following CNS injury and neurodegenerative disease.     

Acute injections of brain-derived neurotrophic factor in a vocal premotor nucleus reversibly disrupt adult birdsong stability and trigger syllable deletion

Behavioral variability serves an essential role in motor learning by enabling sensory feedback to select those motor patterns that minimize error. Birds use auditory feedback to learn how to sing, and their songs lose variability and become highly stereotyped, or crystallized, at the end of a sensitive period for sensorimotor learning. The molecular cues that regulate song variability are not well understood. In other systems, neurotrophins, and brain-derived neurotrophic factor (BDNF) in particular, can mediate various forms of neural plasticity, including sensitive period neural circuit plasticity and activity-dependent synapse formation, and may also influence learning and memory. Here, we have tested the hypothesis that neurotrophin expression in the robust nucleus of the arcopallium (RA), the telencephalic output controlling song, regulates song variability. BDNF and its receptor trkB are expressed in RA, and BDNF expression in RA appears to be highest in juveniles, when song is most variable and plastic, and synapse density highest. Thus, song variability and synaptic connectivity could be enhanced by augmented expression of BDNF in RA. In support of this idea, we found that BDNF injections into the adult RA induced the re-expression of juvenile-like phenotypes, including song variability and an increased synaptic density in RA. Furthermore, BDNF treatment also induced vocal plasticity, characterized by syllable deletions and persistent changes to the song patterns. These results suggest that endogenous BDNF could be a molecular regulator of the song variability essential to vocal plasticity and, ultimately, to song learning.     

Molecular mechanisms coordinating functional and morphological plasticity at the synapse: Role of GluA2/N-cadherin interaction-mediated actin signaling in mGluR-dependent LTD

Long-lasting synaptic plasticity involves changes in both synaptic morphology and electrical signaling (here referred to as structural and functional plasticity). Recent studies have revealed a myriad of molecules and signaling processes that are critical for each of these two forms of plasticity, but whether and how they are mechanistically linked to achieve coordinated changes remain controversial.It is well accepted that functional plasticity at the excitatory synapse is dependent upon the activities of glutamate receptors. While the activation of NMDARs (N-methyl-D-aspartic acid receptors) and/or mGluRs (metabotropic glutamate receptors) is required for the induction of many forms of plasticity, AMPARs (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors), the principal mediators of fast excitatory synaptic transmission, are the ultimate targets of modifications that express functional plasticity. Investigations exploring structural plasticity have been mainly focused on the small membranous protrusions on the dendrites called spines. The morphological regulation of these spines is mediated by the reorganization of the actin cytoskeleton, the predominant structural component of the synapse. In this regard, the Rho family of GTPases, particularly Rac1, RhoA and Cdc42, is found to be the central regulator of spine actin and structural plasticity of the synapse.It is thought that the collaborative interaction between functional and structural factors underlies the sustained or permanent nature of long-lasting synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), the most extensively studied forms of synaptic plasticity widely regarded as cellular mechanisms for learning and memory. However, data specifically pertaining to whether and how these two distinct components are linked at the molecular level remain sparse. In this regard, we have identified a number of synaptic proteins that are involved in both structural and functional changes during mGluR-dependent LTD (mGluR-LTD). Among these are the GluA2 (formerly called GluR2) subunit of AMPARs, Rac1 and Rac1-activated kinases. We have discovered that these proteins interact and reciprocally regulate each other, which led us to hypothesize that the GluA2–Rac1 interaction may serve as a coordinator between functional and morphological plasticity. In this review, we will briefly discuss the available evidence to support such a hypothesis.     

Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons

Long-term depression (LTD) of the synapse formed between cortical pyramidal neurons and striatal medium spiny neurons is central to many theories of motor plasticity and associative learning. The induction of LTD at this synapse is thought to depend upon D(2) dopamine receptors localized in the postsynaptic membrane. If this were true, LTD should be inducible in neurons from only one of the two projection systems of the striatum. Using transgenic mice in which neurons that contribute to these two systems are labeled, we show that this is not the case. Rather, in both cell types, the D(2) receptor dependence of LTD induction reflects the need to lower M(1) muscarinic receptor activity-a goal accomplished by D(2) receptors on cholinergic interneurons. In addition to reconciling discordant tracts of the striatal literature, these findings point to cholinergic interneurons as key mediators of dopamine-dependent striatal plasticity and learning.     

The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses

Neurexins (NXs) and neuroligins (NLs) are transsynaptically interacting cell adhesion proteins that play a key role in the formation, maturation, activity-dependent validation, and maintenance of synapses. As complex alternative splicing processes in nerve cells generate a large number of NX and NLs variants, it has been proposed that a combinatorial interaction code generated by these variants may determine synapse identity and network connectivity during brain development. The functional importance of NXs and NLs is exemplified by the fact that mutations in NX and NL genes are associated with several neuropsychiatric disorders, most notably with autism. Accordingly, major research efforts have focused on the molecular mechanisms by which NXs and NLs operate at synapses. In this review, we summarize recent progress in this field and discuss emerging topics, such as the role of alternative interaction partners of NXs and NLs in synapse formation and function, and their relevance for synaptic plasticity in the mature brain. The novel findings highlight the fundamental importance of NX-NL interactions in a wide range of synaptic functions.     

Two-step wiring plasticity--a mechanism for estrogen-induced rewiring of cortical circuits

Estrogens have been shown to exert powerful effects on cognitive behaviors mediated by several areas of the brain including the cortex. Remodeling of spiny synapses is a key step in the rewiring of neuronal circuitry thought to underlie the processing and storage of information in the forebrain. Whereas estrogen has been shown to regulate synapse structure and function, we are only just starting to understand the molecular and cellular underpinnings of how estrogens can modulate neuronal circuits. Here I will review recent molecular and cellular work that offers a potential mechanism of how estrogen may modulate synapse structure and function of cortical neurons. This mechanism allows cortical neurons to respond to activity-dependent stimuli with greater efficacy in a cellular model termed "Two-Step Wiring Plasticity". This novel form of spine plasticity thus provides insight into how estrogens may modulate the rewiring of neuronal circuits, underlying its ability to influencing cortically based behaviors. This article is part of a Special Issue entitled 'Neurosteroids'.     

Testing the beneficial acclimation hypothesis and its alternatives for locomotor performance

The beneficial acclimation hypothesis (BAH) is controversial. While physiological work all but assumes that the BAH is true, recent studies have shown that support for the BAH is typically wanting. The latter have been criticized for assessing the benefits of developmental plasticity rather than acclimation. Here we examine the BAH within a strong inference framework for five congeneric species of ameronothroid oribatid mites that occupy marine to terrestrial habitats. We do so by assessing responses of maximum speed, optimum temperature, and performance breadth, measured from -10 degrees C to 35 degrees C, to four treatment temperatures (0 degrees , 5 degrees , 10 degrees , and 15 degrees C). We show that the BAH and its alternatives often make similar empirical predictions. Weak beneficial acclimation is characteristic of one of the more marine species. In the other two upper-shore and marine species, evidence exists for deleterious acclimation and the colder-is-better hypothesis. In the two fully terrestrial species, there is no plasticity. Lack of plasticity is beneficial when cue reliability is low or costs of plasticity are high, and the former seems plausible in terrestrial habitats. However, weak plasticity in the upper-shore/marine species and the absence of plasticity in the terrestrial species might also be a consequence of phylogenetic constraint.     

Stress relief may promote the evolution of greater phenotypic plasticity in exotic invasive species: a hypothesis

Invasion ecologists have often found that exotic invaders evolve to be more plastic than conspecific populations from their native range. However, an open question is why some exotic invaders can even evolve to be more plastic given that there may be costs to being plastic. Investigation into the benefits and costs of plasticity suggests that stress may constrain the expression of plasticity (thereby reducing the benefits of plasticity) and exacerbate the costs of plasticity (although this possibility might not be generally applicable). Therefore, evolution of adaptive plasticity is more likely to be constrained in stressful environments. Upon introduction to a new range, exotic species may experience more favorable growth conditions (e.g., because of release from natural enemies). Therefore, we hypothesize that any factors mitigating stress in the introduced range may promote exotic invaders to evolve increased adaptive plasticity by reducing the costs and increasing the benefits of plasticity. Empirical evidence is largely consistent with this hypothesis. This hypothesis contributes to our understanding of why invasive species are often found to be more competitive in a subset of environments. Tests of this hypothesis may not only help us understand what caused increased plasticity in some exotic invaders, but could also tell us if costs (unless very small) are more likely to inhibit the evolution of adaptive plasticity in stressful environments in general.     

Vesicular zinc promotes presynaptic and inhibits postsynaptic long-term potentiation of mossy fiber-CA3 synapse

The presence of zinc in glutamatergic synaptic vesicles of excitatory neurons of mammalian cerebral cortex suggests that zinc might regulate plasticity of synapses formed by these neurons. Long-term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. We tested the hypothesis that zinc within vesicles of mossy fibers (mf) contributes to mf-LTP, a classical form of presynaptic LTP. We synthesized an extracellular zinc chelator with selectivity and kinetic properties suitable for study of the large transient of zinc in the synaptic cleft induced by mf stimulation. We found that vesicular zinc is required for presynaptic mf-LTP. Unexpectedly, vesicular zinc also inhibits?a form of postsynaptic mf-LTP. Because the mf-CA3 synapse provides a major source of excitatory input to the hippocampus, regulating its efficacy by these dual actions, vesicular zinc is critical to proper function of hippocampal circuitry in health and disease.     

Intracellular signaling mechanisms that shape postsynaptic GABAergic synapses

Postsynaptic GABAergic receptors interact with various membrane and intracellular proteins to mediate inhibitory synaptic transmission. They form structural and/or signaling synaptic protein complexes that perform a variety of postsynaptic functions. In particular, the key GABAergic synaptic scaffold, gephyrin, and its interacting partners govern downstream signaling pathways that are essential for GABAergic synapse development, transmission, and plasticity. In this review, we discuss recent researches on GABAergic synaptic signaling pathways. We also outline the main outstanding issues that need to be addressed in this field and highlight the association of dysregulated GABAergic synaptic signaling with the onset of various brain disorders.