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PubMed2005

Synaptic pathways in neural microcircuits.

The functions performed by different neural microcircuits depend on the anatomical and physiological properties of the various synaptic pathways connecting neurons. Neural microcircuits across various species and brain regions are similar in terms of their repertoire of neurotransmitters, their synaptic kinetics, their short-term and long-term plasticity, and the target-specificity of their synaptic connections. However, microcircuits can be fundamentally different in terms of the precise recurrent design used to achieve a specific functionality. In this review, which is part of the TINS Microcircuits Special Feature, we compare the connectivity designs in spinal, hippocampal, neocortical and cerebellar microcircuits, and discuss the different computational challenges that each microcircuit faces.

Animals↗
PubMed2003

Specific localization and timing in neuronal signal transduction mediated by protein-lipid interactions.

A large number of signaling proteins translocate from the cytosol to the plasma membrane in response to receptor and electrical stimuli. The site of translocation to the plasma membrane and the "on" and "off" rates of the translocation process are critical for defining the specificity of the signaling response. In addition to targeting mechanisms based on protein-protein interactions, signaling proteins have evolved a large repertoire of covalent lipid modifications and lipid binding protein modules that regulate reversible membrane association. The time constants of these membrane interactions range from milliseconds to several hours. Here we discuss how diversity in lipid-based membrane anchoring and targeting motifs contributes to plasticity in neuronal signaling by providing local and regional control mechanisms as well as a means to transduce and integrate signals over a broad range of different time scales.

Amino Acid Sequence↗
PubMed2004

Comparative analysis of morphological traits among Drosophila melanogaster and D. simulans: genetic variability, clines and phenotypic plasticity.

The two sibling cosmopolitan species, Drosophila melanogaster and D. simulans, are able to proliferate under very different climatic conditions. This has resulted in local adaptations, which are often arranged in latitudinal clines. Such clines are documented for body weight, wing and thorax length, sternopleural and abdominal bristle number, ovariole number and thoracic pigmentation. The overall magnitude of geographical differentiation is, however, much less in D. simulans than in D. melanogaster, and latitudinal clines are less pronounced. The fact that natural populations live under different climates raises the problem of interaction between temperature and phenotype. The reaction norms of morphometrical traits have been investigated as a function of growth temperature. The shapes of the response curves vary according to the investigated trait. They are generally curvilinear and can be described by calculating characteristic values after polynomial adjustments. For a given trait, the reaction norms of the two species are similar in their shape, although some significant differences may be observed. Within each species, significant differences are also observed between geographic populations: reaction norms are not parallel and the divergence is better marked when more distant populations (e.g., temperate and tropical) are compared. It thus appears that besides mean trait value, phenotypic plasticity is also a target of natural selection. A specific analysis of wing shape variation according to growth temperature was also undertaken. Reaction norms with different shapes may be observed in various parts of the wing: the major effect is found between the basis and the tip of the wing, but in a similar way in the two species. By contrast, some ratios, called wing indices by taxonomists, may exhibit completely different reaction norms in the two species. For a single developmental temperature (25 degrees C) the phenotypic variability of morphometrical traits is generally similar in the two species, and also the genetic variability, estimated by the intraclass correlation. A difference exists, however, for the ovariole number which is less variable in D. simulans. Variance parameters may vary according to growth temperature, and a detailed analysis was made on wing dimensions. An increase of environmental variability at extreme, heat or cold temperatures, has been found in both species. Opposite trends were, however, observed for the genetic variability: a maximum heritability in D. simulans at middle temperatures, corresponding to a minimum heritability in D. melanogaster. Whether such a difference exists for other traits and in other populations deserves further investigations. In conclusion, morphometrical analyses reveal a large amount of significant differences which may be related to speciation and to the divergence of ecological niches. Within each species, numerous geographic variations are also observed which, in most cases, reflect some kinds of climatic adaptation.

Animals↗
PubMed2005

Sigma-1 receptor as regulator of neuronal intracellular Ca2+: clinical and therapeutic relevance.

Preserving brain function and cognitive faculties during aging and psychiatric diseases (e.g. psychotic, anxiety and affective disorders, dementia) is essential for the self-reliance and quality of life of patients. Cognitive loss involves not only memory, but also motor function. The decrease of catecholaminergic and excitatory neurotransmissions, as well as of protein phosphorylation, have currently been identified as prominent biological markers of the above-mentioned diseases. Such deleterious biological events are well known to occur downstream of a progressive decline of intracellular Ca2+ signalling. This latter constitutes a key target for the neuronal plasticity that has also been reported during aging and psychiatric disorders. Most of the medicines used in psychiatry are active on the sigma-1 receptor. This membrane bound receptor is widely distributed in memory-associated cortical and motor-related brainstem areas, prompting the hypothesis that it might contribute to the pathophysiology of these behavioural brain diseases. The sigma-1 receptor is characterized by a unique mode of action by regulating both Ca2+ entry at the plasma membrane level (i.e. via potassium channels, voltage-sensitive Ca2+ channels) and Ca2+ mobilization from endoplasmic stores [i.e. via Ins(1,4,5)P3 receptors]. This review presents recent data supporting the notion that drugs acting via the endoplasmic reticulum-coupled sigma-1 receptor might reverse these deleterious events by restoring both extra- and intra-cellular Ca(2+)-dependent neuronal responses.

Aging↗
PubMed1998

Induction of long-term potentiation in vivo regulates alternate splicing to alter syntaxin 3 isoform expression in rat dentate gyrus.

The regulation and specificity of the interactions between the proteins involved in neurotransmitter release are obvious targets for the cellular control of synaptic plasticity. Previous research has identified one of these proteins, syntaxin 1B, as a potential target for mediating the propagation of synaptic plasticity through neural networks. The expression of syntaxin 1B is modified in the hippocampus after the induction of long-term potentiation (LTP) and during learning. Here, we describe the identification of two other members of the syntaxin family from rat brain, syntaxins 3A and 3B, and show that they are generated from the same gene by alternate splicing. In situ hybridization and immunohistochemical staining confirm the expression of syntaxins 3A and 3B in the adult rat brain. The transcripts and proteins show a lower abundance but a similar pattern of expression as syntaxins 1A and 1 B. By using quantitative competitive PCR, we show that the mRNAs that encode syntaxins 1B and 3A are increased in dentate granule cells 6 h after the induction of LTP in vivo, whereas syntaxin 3B mRNA is decreased as rapidly as 30 min, and lasts for at least 6 h, after the induction of LTP. These findings identify coordinated changes in the expression of several syntaxin isoforms with different substrate specificities and suggest that regulation of the splicing machinery by LTP induction is one of the diverse strategies used during the long-term modification of the synapse in the vertebrate nervous system.

Alternative Splicing↗
PubMed2000

Pain mechanisms and management: a central perspective.

Although pain is always intense and unpleasant, the capacity to experience this sensation is, under normal circumstances, fundamental to the preservation of bodily integrity. Clinically, however, after injury to peripheral tissue or directly to the nervous system, spontaneous and evoked pain manifest that serve no physiologic function, are crippling to patients, and are difficult to treat. Here, we review the specific role of the dorsal horn of the spinal cord in the mechanisms of nociceptive protective pain and the spinal plasticity that occurs after nerve and tissue injury. This spinal neuronal plasticity is shown to be a key contributor to pathologic pain hypersensitivity. The potential for the molecular mechanisms responsible for the spinal plasticity in revealing new targets for future treatment is also discussed.

Animals↗
PubMed1998

Disease conditions and subclinical infections of the platypus (Ornithorhynchus anatinus).

Before the arrival of European settlers in Australia, the platypus, Ornithorhynchus anatinus, probably suffered from little disease. Among other things, European settlement has involved substantial environmental perturbation, introduction of large predators, introduction of motor vehicles and translocation of potential pathogens. As a result, platypuses are now killed by motor vehicles, dogs, foxes and discarded plastic litter. Information programmes targeting appropriate segments of the public would help reduce these unnecessary deaths. The enigmatic disease, ulcerative mycosis, caused by Mucor amphibiorum, has been the subject of scientific investigation in Tasmania for the past 15 years. The apparent recent acceleration in its spread has sounded a warning and more intensive investigation is warranted. The possibility that this pathogen has been translocated from subtropical to temperate Tasmania, Australia, with green free frogs in banana shipments further emphasizes the role of humans in threatening the welfare of the platypus. Recommendations are made in relation to appropriate measures that could be taken to ameliorate disease and trauma in this species.

Animal Diseases↗
PubMed2003

CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects.

The treatment of memory disorders, such as the gradual weakening of memory with age, the ravages of Alzheimer's disease and the cognitive deficits in various forms of mental retardation, may greatly benefit from a better understanding of the molecular and cellular mechanisms of memory formation. There is increasing interest in the possibility of pharmacologically enhancing learning and memory even in the absence of specific anatomically evident pathology. Substantial evidence in experimental systems ranging from molluscs to humans indicates that the cAMP response element binding protein (CREB) is a core component of the molecular switch that converts short- to long-term memory. Recent studies have greatly strengthened and refined our understanding of the role of CREB in learning and memory in mammals, in addition to providing greater insight into the molecular mechanisms of CREB regulation and function. This involvement of CREB and the upstream signalling pathways leading to its activation in learning-associated plasticity makes them attractive targets for drugs aimed at improving memory function, in both diseased and healthy individuals. However, CREB and its close relatives cAMP response element modulator and activating transcription factor-1 are ubiquitous proteins with several critical functions. This creates hurdles that the authors believe may limit the usefulness of CREB per se as a target for the development of memory-enhancing drugs, and focus on components of the upstream signalling pathways or on specific downstream targets will be required.

Amino Acid Sequence↗
PubMed2006

Interaction of Kv3 potassium channels and resurgent sodium current influences the rate of spontaneous firing of Purkinje neurons.

Purkinje neurons spontaneously generate action potentials in the absence of synaptic drive and thereby exert a tonic, yet plastic, input to their target cells in the deep cerebellar nuclei. Purkinje neurons express two ionic currents with biophysical properties that are specialized for high-frequency firing: resurgent sodium currents and potassium currents mediated by Kv3.3. How these ionic currents determine the intrinsic activity of Purkinje neurons has only partially been understood. Purkinje neurons from mutant mice lacking Kv3.3 have a reduced rate of spontaneous firing. Dynamic-clamp recordings demonstrated that normal firing rates are rescued by inserting artificial Kv3 currents into Kv3.3 knock-out Purkinje neurons. Numerical simulations indicated that Kv3.3 increases the spontaneous firing rate via cooperation with resurgent sodium currents. We conclude that the rate of spontaneous action potential firing of Purkinje neurons is controlled by the interaction of Kv3.3 potassium currents and resurgent sodium currents.

Action Potentials↗
PubMed2003

Neural GPI-anchored cell adhesion molecules.

When first identified, neural cell adhesion molecules (neural CAMs) were thought to act simply by providing cell surfaces with differential adhesion properties. In the decades following the identification of the first neural CAMs, it has been realized that these proteins are actually involved in very complex processes such as axon guidance, neuronal migration, neurite outgrowth and fasciculation, target selection, synapse formation, plasticity and more recently, the maintenance of the integrity of myelinated fibers. In this review we will summarize work relating to glycosylphosphatidylinositol-anchored CAMs (GPI-CAMs) and will highlight expression/function issues, protein interactions and the role of the GPI in signaling.

Animals↗
PubMed2002

Regulation of synaptic connectivity: levels of Fasciclin II influence synaptic growth in the Drosophila CNS.

Much of our understanding of synaptogenesis comes from studies that deal with the development of the neuromuscular junction (NMJ). Although well studied, it is not clear how far the NMJ represents an adequate model for the formation of synapses within the CNS. Here we investigate the role of Fasciclin II (Fas II) in the development of synapses between identified motor neurons and cholinergic interneurons in the CNS of Drosophila. Fas II is a neural cell adhesion molecule homolog that is involved in both target selection and synaptic plasticity at the NMJ in Drosophila. In this study, we show that levels of Fas II are critical determinants of synapse formation and growth in the CNS. The initial establishment of synaptic contacts between these identified neurons is seemingly independent of Fas II. The subsequent proliferation of these synaptic connections that occurs postembryonically is, in contrast, significantly retarded by the absence of Fas II. Although the initial formation of synaptic connectivity between these neurons is seemingly independent of Fas II, we show that their formation is, nevertheless, significantly affected by manipulations that alter the relative balance of Fas II in the presynaptic and postsynaptic neurons. Increasing expression of Fas II in either the presynaptic or postsynaptic neurons, during embryogenesis, is sufficient to disrupt the normal level of synaptic connectivity that occurs between these neurons. This effect of Fas II is isoform specific and, moreover, phenocopies the disruption to synaptic connectivity observed previously after tetanus toxin light chain-dependent blockade of evoked synaptic vesicle release in these neurons.

Animals↗
PubMed2003

The Homer family and the signal transduction system at glutamatergic postsynaptic density: potential role in behavior and pharmacotherapy.

The postsynaptic density (PSD) is an ultrastructural specialization of the glutamatergic excitatory synapses, at the cytosolic surface of the postsynaptic membrane of dendritic spines. The PSD is a highly organized transductional machinery that tunes the excitatory signaling from presynaptic terminals. Hundreds of proteins have been isolated in the PSD including glutamate receptors, kinases, as well as scaffolding, association, and cytoskeleton proteins. Homer is a family of PSD proteins involved in the cross-interaction between metabotropic glutamate receptors and intracellular signal transduction systems. Homer1a (H1a) is the only inducible isoform of the Homer family, whereas all the other isoforms (H1b/c, H2, and H3) are constitutively expressed. Further, H1a exhibits a ligand-binding motif but not the homomultimerization domain. H1a induction disrupts the clusters of PSD factors formed by constitutive Homers. Several stimuli have been demonstrated to induce H1a gene expression in the central nervous system, including the administration of antipsychotics. Homer-regulated PSD remodeling may represent a mechanism of synaptic plasticity and a putative target for both pharmacotherapy and pharmacogenomics of behavioral disorders.

Animals↗
PubMed1992

Antibody neutralization of neurite growth inhibitors from oligodendrocytes results in expanded pattern of postnatally sprouting retinocollicular axons.

After early postnatal ablation of one superior colliculus together with the ipsilateral eye in Syrian hamsters, retinofugal fibers abnormally cross the tectal midline and innervate the remaining superior colliculus. The fibers of this aberrant decussation are confined mainly to the superficial gray layer, with little ingrowth or termination in the deeper stratum opticum; laterally, most termination is in the superficial part of the superficial gray. Establishment of this abnormal pattern is temporally correlated with the appearance of oligodendrocytes at progressively more superficial locations in the colliculus. Oligodendrocytes express, on their surface, molecules that are inhibitory to neurite growth. This raises the possibility that their differential distribution in the superior colliculus during growth of retinal fibers is causally involved in the generation of the observed termination pattern. We tested this hypothesis by applying the monoclonal antibody IN-1, which neutralizes this inhibitory activity, during the time of postnatal fiber growth and terminal arbor formation. We found that in the presence of IN-1, but not a control antibody, recrossing retinofugal fibers, observed at postnatal day 12, traverse the stratum opticum as well as the superficial gray, with greater depth of termination in superficial gray and stratum opticum. This pattern resembles that of the normal contralateral retinotectal projection. The results indicate that neurite growth inhibitors expressed by oligodendrocytes are responsible for restricting the innervation of a target area in postnatal plasticity.

Animals↗
PubMed1999

Role of astroglia in estrogen regulation of synaptic plasticity and brain repair.

Astroglia are targets for estrogen and testosterone and are apparently involved in the action of sex steroids on the brain. Sex hormones induce changes in the expression of glial fibrillary acidic protein, the growth of astrocytic processes, and the degree of apposition of astroglial processes to neuronal membranes in the rat hypothalamus. These changes are linked to modifications in the number of synaptic inputs to hypothalamic neurons. These findings suggest that astrocytes may participate in the genesis of androgen-induced sex differences in synaptic connectivity and in estrogen-induced synaptic plasticity in the adult brain. Astrocytes and tanycytes may also participate in the cellular effects of sex steroids by releasing neuroactive substances and by regulating the local accumulation of specific growth factors, such as insulin-like growth factor-I, that are involved in estrogen-induced synaptic plasticity and estrogen-mediated neuroendocrine control. Astroglia may also be involved in regenerative and neuroprotective effects of sex steroids, since astroglia formation after brain injury or after peripheral nerve axotomy is regulated by sex hormones. Furthermore, the expression of aromatase, the enzyme that produces estrogen, is induced de novo in astrocytes in lesioned brain areas of adult male and female rodents. Since astroglia do not express aromatase under normal circumstances, the induction of this enzyme may be part of the program of glial activation to cope with the new conditions of the neural tissue after injury. Given the neuroprotective and growth-promoting effects of estrogen after injury, the local production of this steroid may be a relevant component of the reparative process.

Animals↗
PubMed1991

Topographic maps of human motor cortex in normal and pathological conditions: mirror movements, amputations and spinal cord injuries.

We studied motor evoked potentials to transcranial magnetic stimulation in patients with unilateral upper limb amputations, complete T10-T12 spinal cord transection, and congenital mirror movements and in controls. Different muscles in the trunk and upper and lower extremities were evaluated at rest. In controls, muscles could be activated with stimulation of regions several centimeters wide. These areas overlapped extensively when muscles studied were from the same limb and shifted positions abruptly when muscles were from different limbs. Distal muscles were easier to activate than proximal muscles and normally evidenced exclusively a contralateral representation. Congenital defects in motor control in patients with mirror movements resulted in marked derangement of the map of outputs of distal hand muscles with enlarged and ipsilateral representations. Peripheral lesions, either acquired (amputations) or congenital (congenital absence of a limb), resulted in plastic reorganization of motor outputs targeting muscles immediately proximal to the stump. Central nervous system lesions (i.e., spinal cord injury producing paraplegia) also resulted in enlargement of the map of outputs targeting muscles proximal to the lesion. These results indicate that magnetic stimulation is a useful non-invasive tool for exploring plastic changes in human motor pathways following different types of injury.

Adult↗
PubMed1999

Molecular analysis of developmental plasticity in neocortex.

Gene expression studies indicate that during activity-dependent developmental plasticity, N-methyl-D-aspartate receptor activation causes a Ca(2+)-dependent increase in expression of transcription factors and their downstream targets. The products of these plasticity genes then operate collectively to bring about the structural and functional changes that underlie ocular dominance plasticity in visual cortex. Identifying and characterizing plasticity genes provides a tool for molecular dissection of the mechanisms involved. Members of second-messenger pathways identified in adult plasticity paradigms and elements of the transmission machinery are the first candidate plasticity genes tested for their role in activity-dependent developmental plasticity. Knockout mice with deletions of such genes have allowed analyzing their function in the context of different systems and in different paradigms. Studies of mutant mice reveal that activity-dependent plasticity is not necessarily a unified phenomenon. The relative importance of a gene can vary with the context of its expression during different forms of plasticity. Forward genetic screens provide additional new candidates for testing, some with well-defined cellular functions that provide insight into possible plasticity mechanisms.

Animals↗
PubMed2000

Sequential activation of the 5-HT1(A) serotonin receptor and TrkB induces the serotonergic neuronal phenotype.

Serotonin (5-HT) is an important factor controlling survival, differentiation, and plasticity of neurons in serotonergic target regions of the brain and has been implicated in major psychiatric and autonomic disorders. Relatively little is known, however, of factors controlling differentiation and plasticity of developing and adult 5-HT neurons. We show now that 5-HT, the 5-HT1(A) receptor, brain-derived neurotrophic factor (BDNF), and its receptor, trkB, form an auto/paracrine loop for the regulation of the serotonergic phenotype. Serotonin applied to cultures from E14 rat raphe increased numbers of neurons expressing serotonergic markers in a dose-dependent manner. Agonists of the 5-HT1(A) receptor, BP-554 and 8-OH-DPAT, but not agonists of the 5-HT1(B) and 5-HT1(D) receptors, mimicked this effect, while the specific 5-HT1(A) antagonist, WAY-100635, inhibited it. Serotonin also increased BDNF mRNA and protein in embryonic raphe cultures. Induction of serotonergic markers by serotonin was suppressed by a trkB-IgG fusion protein but not by trkC-IgG. Taken together, our data indicate that serotonin acts on 5-HT1(A) autoreceptors, causing up-regulation of BDNF, which activates trkB to promote serotonergic phenotype-specific markers.

Animals↗
PubMed1998

Differential distribution, affinity and plasticity of dopamine D-1 and D-2 receptors in the target sites of the mesolimbic system in an animal model of ADHD.

The distribution of dopamine (DA) D-1 and D-2 receptors has been studied by autoradiography in the anterior forebrain of the pre-hypertensive spontaneously hypertensive rat (SHR) as an animal model of attention-deficit hyperactivity disorder (ADHD) in children. Juvenile male SHR and Wistar Kyoto (WKY) controls were given either vehicle or the DA re-uptake blocker methylphenidate (MP; 3 mg/kg, i.p.), daily during a 2-week period. A saturation analysis for the D-1 receptor subfamily was carried out with 0.1-5.0 nM of [3H]SCH23390 and two competition studies for the D-2 receptor subfamily with 4 nM of [3H]raclopride or 5 nM of [3H]quinpirole were carried out with unlabelled spiperone and 7-OH-DPAT as unlabelled displacers on cryostat coronal sections of the anterior forebrain. Quantitative receptor autoradiography and computer-assisted image analysis with reference to co-exposed 3H-microscale standards showed in vehicle-treated SHR higher density of DA D-1/D-5 receptor subtypes in the caudate-putamen (CPU), the nucleus accumbens (ACB) core and shell and the olfactory tubercle (OT), which was associated to a lower affinity. MP treatment normalised the DA D-1/D-5 receptors by decreasing the number of binding sites and increasing the affinity to control level. In addition, MP treatment 'down-regulated' DA D-2/D-4 subtypes in the CPU, ACB and OT, and 'up-regulated' mostly D-3 subtype in CPU, ACB, OT in both rat lines and in the globus pallidus, ventral pallidum and lateral septum in WKY rats only. In contrast, D-3 receptors were 'down-regulated' in the islands of Calleja in both rat lines. Moreover, regional cross-correlative analyses revealed a modulatory influence of DA receptors in the cross-talk within the anterior forebrain, which was altered in the SHR. Thus, the differential distribution and regulation of DA receptor subtypes following DA re-uptake blocker as well as the different regional cross-talk in the target sites of nigrostriatal and mesolimbic DA systems lend support to the DA hypothesis of ADHD in children.

Animals↗