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PubMed2006

Induction of brain-derived neurotrophic factor by leptin in the ventromedial hypothalamus.

Leptin, an adipocyte-derived hormone, reduces food intake by regulating orexigenic and anorexigenic factors in the hypothalamus. Although brain-derived neurotrophic factor is an important anorexigenic factor in the hypothalamus, little is known about the regulation of brain-derived neurotrophic factor expression by leptin in the hypothalamus. In the present study, we examined the effect of leptin on the expression of brain-derived neurotrophic factor in the hypothalamus. I.V. administration of leptin (10 microg/g) led to the increase in the expression of brain-derived neurotrophic factor mRNA, which was observed in the dorsomedial part of the ventromedial hypothalamic nucleus. The increased expression of brain-derived neurotrophic factor mRNA was detected in phosphorylated signal transducer and activator of transcription 3-positive neurons, suggesting that leptin induced brain-derived neurotrophic factor expression in neurons of the dorsomedial part of the ventromedial hypothalamic nucleus. In addition, the expression of brain-derived neurotrophic factor was increased at the protein level in the ventromedial hypothalamic nucleus of leptin-injected mice. Interestingly, brain-derived neurotrophic factor-positive fibers also increased in the ventromedial hypothalamic nucleus and dorsomedial hypothalamic nucleus of leptin-injected mice, which were in close apposition to tyrosine kinase receptor B-immunoreactive neurons and colocalized with synaptophysin, a marker of presynaptic terminals. These results suggest that leptin induces brain-derived neurotrophic factor expression in the dorsomedial part of the ventromedial hypothalamic nucleus and brain-derived neurotrophic factor may exert as anorexigenic factors possibly through the activation of tyrosine kinase receptor B in the ventromedial hypothalamic nucleus and dorsomedial hypothalamic nucleus.

Animals↗
PubMed2006

Frequency-dependent modulation of glycine receptor activation recorded from the zebrafish larvae hindbrain.

In vertebrates, most glycinergic inhibitory neurons discharge phasically at a relatively low frequency. Such a pattern of glycine liberation from presynaptic terminals may affect the kinetics of post-synaptic glycine receptors. To examine this influence, we have analyzed the behavior of glycine receptors in response to repetitive stimulation at frequencies at which consecutive outside-out currents did not superimpose (0.5-4 Hz). Neurotransmitter release was mimicked on outside-out patches from zebrafish hindbrain Mauthner cells using fast flow application techniques. The amplitude of outside-out currents evoked by short (1 ms) repetitive applications of a saturating concentration (3 mM) of glycine remained unchanged for application frequencies 1 Hz. Glycine-evoked current simulations using a simple Markov model describing zebrafish glycine receptor kinetic behavior, indicates that this down-regulation of glycine receptor efficacy is due to a progressive accumulation of the receptors in a long lasting desensitization state. Our simulations suggest that this down-regulation can occur even when spontaneous inhibitory currents were generated randomly at a frequency>1 Hz.

Animals↗
PubMed2006

Hippocampal synapsin I, growth-associated protein-43, and microtubule-associated protein-2 immunoreactivity in learned helplessness rats and antidepressant-treated rats.

Learned helplessness rats are thought to be an animal model of depression. To study the role of synapse plasticity in depression, we examined the effects of learned helplessness and antidepressant treatments on synapsin I (a marker of presynaptic terminals), growth-associated protein-43 (GAP-43; a marker of growth cones), and microtubule-associated protein-2 (MAP-2; a marker of dendrites) in the hippocampus by immunolabeling. (1) Learned helplessness rats showed significant increases in the expression of synapsin I two days after the attainment of learned helplessness, and significant decreases in the protein expression eight days after the achievement of learned helplessness. Subchronic treatment of naïve rats with imipramine or fluvoxamine significantly decreased the expression of synapsin I. (2) Learned helplessness increased the expression of GAP-43 two days and eight days after learned helplessness training. Subchronic treatment of naïve rats with fluvoxamine but not imipramine showed a tendency to decrease the expression of synapsin I. (3) Learned helplessness rats showed increased expression of MAP-2 eight days after the attainment of learned helplessness. Naïve rats subchronically treated with imipramine showed a tendency toward increased expression of MAP-2, but those treated with fluvoxamine did not. These results indicate that the neuroplasticity-related proteins synapsin I, GAP-43, and MAP-2 may play a role in the pathophysiology of depression and the mechanisms of antidepressants.

Analysis of Variance↗
PubMed2006

Reduced psychostimulant effects on dopamine dynamics in the nucleus accumbens of mu-opioid receptor knockout mice.

Dopamine neurotransmission in the nucleus accumbens plays a pivotal role in the reinforcing properties of drugs of abuse. Two interacting processes regulate nucleus accumbens dopamine overflow: release of dopamine from presynaptic terminals and the subsequent reuptake by dopamine transporters. Opioid neurotransmission, primarily through mu-opioid receptors has also been strongly implicated in drug reward. We have previously shown that mice lacking the mu-opioid receptor display decreased cocaine self-administration. In addition, we found decreased impulse activity of midbrain dopaminergic neurons and an increased GABAergic input to these neurons in mu-opioid receptor knockout mice. In the present study we investigated whether these changes in dopaminergic cell bodies are accompanied by altered dopamine dynamics at the terminal level. To that aim, we measured nucleus accumbens dopamine overflow using fast scan cyclic voltammetry. Our data demonstrate that in mu-opioid receptor knockout mice 1) the reuptake of dopamine in the nucleus accumbens is slower, and 2) the relative effect of cocaine and amphetamine on the reuptake of dopamine is smaller compared with wild type mice. These data provide a mechanism for the decreased reinforcing properties of cocaine observed in mu-opioid receptor knockout mice.

Amphetamine↗
PubMed2006

Neurochemical characterization of pathways expressing plasma membrane monoamine transporter in the rat brain.

Neurotransmitter transporters play an important role in the control of synaptic transmission by ensuring the clearance of transmitters liberated in the synaptic cleft. In the case of monoaminergic neurotransmitters, this clearance is carried out by high-affinity reuptake transporters located in the plasma membrane of the presynaptic terminals. Recently plasma membrane monoamine transporter (PMAT), a transporter from the SLC29 (equilibrative nucleoside transporter) family, was shown to transport in vitro monoaminergic neurotransmitters, in particular dopamine and serotonin, nearly as efficiently as the high-affinity transporters. This transporter, well expressed in CNS, represents an interesting candidate for the control and modulation of aminergic pathways. We performed an extensive study of the distribution of PMAT in the rat brain. Our results highlight PMAT expression in brain regions which play a pivotal role in significant CNS functions and human neuropathologies. Using in situ hybridization immunohistochemistry co-labeling, PMAT mRNA was found in various neuron subtypes, including glutamatergic neurons of the hippocampus, mitral cells of the olfactory bulbs and GABAergic neurons in the substantia nigra pars reticulata and hypothalamus. Paradoxically, rat PMAT mRNA was found in some but not all monoaminergic nuclei. It was on the contrary predominantly expressed in major cholinergic groups throughout the brain, including brainstem motor nuclei, components of the basal forebrain cholinergic system and cholinergic interneurons of the striatum. These systems, implicated in locomotion, associative and spatial memory and reward-related learning, are disrupted at early stages of Parkinson's and Alzheimer's disease. Taken together, our observations support a role for PMAT in monoamine uptake in cholinergic neurons.

Animals↗
PubMed2007

The actin binding domain of ACF7 binds directly to the tetratricopeptide repeat domains of rapsyn.

Formation of the neuromuscular junction requires the release of agrin from the presynaptic terminal of motor neurons. Clustering of acetylcholine receptors (AChRs) on the postsynaptic sarcolemma is initiated by agrin-dependent activation of the muscle-specific kinase. While the postsynaptic scaffolding protein rapsyn is vital for high density AChR aggregation, little is known about the mechanism through which AChRs are immobilized on the postsynaptic membrane. Ultrastructural and immunohistochemical studies of rat skeletal muscle have suggested that AChRs are anchored to a membrane-associated cytoskeleton that contains spectrin-like proteins and is thus similar to that of the human erythrocyte [Bloch RJ, Bezakova G, Ursitti JA, Zhou D, Pumplin DW (1997) A membrane skeleton that clusters nicotinic acetylcholine receptors in muscle. Soc Gen Physiol Ser 52:177-195]. We are studying a protein of the spectrin superfamily, ACF7 (also known as MACF), as a postsynaptic cytoskeletal component of the neuromuscular junction. ACF7 has multiple cytoskeleton-binding domains, including an N-terminal actin-binding domain that, we postulate, may interact with rapsyn, the scaffolding protein that binds directly to AChRs. To test this hypothesis, we co-expressed fragments of these molecules in cultured fibroblasts and assessed their co-distribution and interaction using confocal microscopy and co-immunoprecipitation. We demonstrate that the actin-binding domain of ACF7 specifically interacts with the tetratricopeptide repeat domains of rapsyn. Furthermore, we show using surface plasmon resonance and blot overlay that the actin-binding domain of ACF7 binds directly to rapsyn. These results suggest that, in mammalian skeletal muscle, AChRs are immobilized in the membrane through rapsyn-mediated anchoring to an ACF7-containing network that in turn is linked to the actin cytoskeleton.

Actins↗
PubMed2005

Amnestic effect of intrahippocampal AM251, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats.

CB1 is the most abundant metabotropic receptor of the brain, being found in areas classically involved in learning and memory and present at higher density at presynaptic terminals. Different sets of evidence support the idea that endogenous ligands (endocannabinoids) to the CB1 receptors act as modulators of neurotransmission. In hippocampus, endocannabinoids seem to act as retrograde messengers mediating down-regulation of GABA release. Previous reports have described a cognitive impairment effect of cannabinoid agonists, or facilitation by antagonists. The scope of the present study is to investigate the effect of intrahippocampal administration of the CB1-selective antagonist, AM251, in two behavioral tasks. One hundred and twelve male Wistar rats with bilateral cannulae implanted in the CA1 region of the dorsal hippocampus were trained in a step-down inhibitory avoidance task (IA, footshock, 0.5 mA) or an open field habituation task (OF). Immediately, after training, animals received an infusion of 0.55, 5.5, and 55.5 ng/side of AM251 (Tocris), or its vehicle (DMSO/saline), via these cannulae. Our results show that AM251 disrupted memory consolidation of the IA task, but not the OF task, an effect that seems to be purely mnemonic since the drug showed no motor performance effects. Only the intermediate dose (5.5 ng/side) of AM251 was effective in IA and the absence of effect with the larger dose may be the consequence of non-specific binding. The fact that OF was not affected raises the possibility that this endogenous system requires some degree of aversiveness to be recruited. We propose that increased levels of endogenous cannabinoids in the hippocampus, following a training session, contribute to facilitate memory consolidation, a process that may have been disrupted with AM251.

Animals↗
PubMed2005

N-methyl-D-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention?

Excitatory synaptic transmission in the central nervous system (CNS) is mediated by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and non-NMDA (AMPA and KA) receptors. Extracellular signals control diverse neuronal functions and are responsible for mediating activity-dependent changes in synaptic strength and neuronal survival. Influx of extracellular calcium ([Ca(2+)](e)) through the NMDA receptor (NMDAR) is required for neuronal activity to change the strength of many synapses. At the molecular level, the NMDAR interacts with signaling modules, which, like the mitogen-activated protein kinase (MAPK) superfamily, transduce excitatory signals across neurons. Recent burgeoning evidence points to the fact that MAPKs play a crucial role in regulating the neurochemistry of NMDARs, their physiologic and biochemical/biophysical properties, and their potential role in pathophysiology. It is the purpose of this review to discuss: (i) the MAPKs and their role in a plethora of cellular functions; (ii) the role of MAPKs in regulating the biochemistry and physiology of NMDA receptors; (iii) the kinetics of MAPK-NMDA interactions and their biologic and neurochemical properties; (iv) how cellular signaling pathways, related cofactors and intracellular conditions affect NMDA-MAPK interactions and (v) the role of NMDA-MAPK pathways in pathophysiology and the evolution of disease conditions. Given the versatility of the NMDA-MAPK interactions, the NMDA-MAPK axis will likely form a neurochemical target for therapeutic interventions.

Animals↗
PubMed2006

The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia.

The dopamine hypothesis of schizophrenia has been the most influential since the 1970s. Normally, the prefrontal dopamine system suppressively controls the limbic dopamine system. Since the activities of prefrontal dopaminergic neurons are reduced in schizophrenia, the suppressive effect of the prefrontal area on the limbic system is reduced, and activities of the limbic dopamine system are enhanced. Reduced activities of the prefrontal dopamine system contribute to negative symptoms and cognitive disorders, and increased activities of the limbic dopamine system induce positive symptoms. While the dopamine hypothesis explains the relationship between dopamine kinetics and psychiatric symptoms in schizophrenia, it is not a direct explanation of its etiology. The cause of the abnormal activities of dopaminergic neurons in schizophrenia and its resultant symptoms are unknown. Since the late 1980s, it has been revealed that the n-3 fatty acid concentration is reduced in the plasma and erythrocyte membranes of schizophrenic patients and that the administration of n-3 fatty acids may be effective for the treatment of schizophrenia. Whether or not n-3 fatty acid deficiency plays a direct role in schizophrenia etiology, and the mechanisms underlying their therapeutic effect have yet to be clarified. Recently, the dopamine hypothesis and n-3 fatty acid hypothesis have been suggested to represent different aspects of the same pathology of schizophrenia. In schizophrenia, the brain concentrations of certain n-3 fatty acids are decreased. In rodents, n-3 fatty acid deficiency has been shown to cause decreases in dopamine concentration, number of vesicles and D2 receptors at prefrontal presynaptic terminals. The following minireview provides a summary of findings from n-3 fatty acid deficient animal models and their relevance to schizophrenia pathology is discussed.

Dopamine↗
PubMed2005

Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function.

Cell adhesion represents the most direct way of coordinating synaptic connectivity in the brain. Recent evidence highlights the importance of a trans-synaptic interaction between postsynaptic neuroligins and presynaptic neurexins. These transmembrane molecules bind each other extracellularly to promote adhesion between dendrites and axons. This signals the recruitment of presynaptic and postsynaptic molecules to form a functional synapse. Remarkably, neuroligins alone can induce the formation of fully functional presynaptic terminals in contacting axons. Conversely, neurexins alone can induce postsynaptic differentiation and clustering of receptors in dendrites. Therefore, the neuroligin-neurexin interaction has the unique ability to act as a bi-directional trigger of synapse formation. Here, we review several recent studies that offer clues as to how these proteins form synapses and how they might function in the brain to establish and modify neuronal network properties and cognition.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed2006

Is brain estradiol a hormone or a neurotransmitter?

Mounting evidence indicates that, besides their well-known hormonal mode of action at the genetic level, estrogens such as 17beta-estradiol also influence brain function by direct effects on neuronal membranes. Experimentally induced rapid changes in estradiol bioavailability in the brain have been shown to alter the expression of male sexual behavior significantly within minutes--probably too quickly to be accounted for by conventional genetic mechanisms. In parallel, recent studies indicate that aromatase, the enzyme that converts testosterone to estradiol in the brain, is expressed in presynaptic terminals and modulated within minutes by Ca(2+)-dependent phosphorylation. In this article, we develop the hypothesis that brain estrogens display many, if not all, functional characteristics of neuromodulators or even neurotransmitters.

Animals↗
PubMed1996

False-negative hydroxyamphetamine (Paredrine) test in acute Horner's syndrome.

PURPOSE: To describe a false-negative hydroxyamphetamine test. METHOD: Two patients with acute unilateral Horner's syndrome whose pupils initially dilated equally to hydroxyamphetamine had pharmacologic localization to the postganglionic nerve in the second week following the onset of symptoms. RESULTS: Neuroimaging confirmed the postganglionic location in both cases. CONCLUSION: Falsely negative localization with hydroxyamphetamine can occur during the first week after injury, during which time the function of the boutons at the presynaptic terminal is lost.

Acute Disease↗
PubMed2000

Astroglial expression of human alpha(1)-antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice.

Proteases and their inhibitors play key roles in physiological and pathological processes. Cerebral amyloid plaques are a pathological hallmark of Alzheimer's disease (AD). They contain amyloid-ss (Ass) peptides in tight association with the serine protease inhibitor alpha(1)-antichymotrypsin.(1,2) However, it is unknown whether the increased expression of alpha(1)-antichymotrypsin found in AD brains counteracts or contributes to the disease. We used regulatory sequences of the glial fibrillary acidic protein gene(3) to express human alpha(1)-antichymotrypsin (hACT) in astrocytes of transgenic mice. These mice were crossed with transgenic mice that produce human amyloid protein precursors (hAPP) and Ass in neurons.(4,5) No amyloid plaques were found in transgenic mice expressing hACT alone, whereas hAPP transgenic mice and hAPP/hACT doubly transgenic mice developed typical AD-like amyloid plaques in the hippocampus and neocortex around 6 to 8 months of age. Co-expression of hAPP and hACT significantly increased the plaque burden at 7 to 8, 14, and 20 months. Both hAPP and hAPP/hACT mice showed significant decreases in synaptophysin-immunoreactive presynaptic terminals in the dentate gyrus, compared with nontransgenic littermates. Our results demonstrate that hACT acts as an amyloidogenic co-factor in vivo and suggest that the role of hACT in AD is pathogenic.

Alzheimer Disease↗
PubMed1999

Elimination of the class A scavenger receptor does not affect amyloid plaque formation or neurodegeneration in transgenic mice expressing human amyloid protein precursors.

The class A scavenger receptor (SR) is expressed on reactive microglia surrounding cerebral amyloid plaques in Alzheimer's disease (AD). Interactions between the SR and amyloid beta peptides (Abeta) in microglial cultures elicit phagocytosis of Abeta aggregates and release of neurotoxins. To assess the role of the SR in amyloid clearance and Abeta-associated neurodegeneration in vivo, we used the platelet-derived growth factor promoter to express human amyloid protein precursors (hAPPs) in neurons of transgenic mice. With increasing age, hAPP mice develop AD-like amyloid plaques. We bred heterozygous hAPP (hAPP(+/-)) mice that were wild type for SR (SR(+/+)) with SR knockout (SR(-/-)) mice. Crosses among the resulting hAPP(+/-)SR(+/-) offspring yielded hAPP(+/-) and hAPP(-/-) littermates that were SR(+/+) or SR(-/-). These second-generation mice were analyzed at 6 and 12 months of age for extent of cerebral amyloid deposition and loss of synaptophysin-immunoreactive presynaptic terminals. hAPP(-/-)SR(-/-) mice showed no lack of SR expression, plaque formation, or synaptic degeneration, indicating that lack of SR expression does not result in significant accumulation of endogenous amyloidogenic or neurotoxic factors. In hAPP(+/-) mice, ablation of SR expression did not alter number, extent, distribution, or age-dependent accumulation of plaques; nor did it affect synaptic degeneration. Our results do not support a critical pathogenic role for microglial SR expression in neurodegenerative alterations associated with cerebral beta amyloidosis.

Alzheimer Disease↗
PubMed2004

Facilitation through buffer saturation: constraints on endogenous buffering properties.

Synaptic facilitation (SF) is a ubiquitous form of short-term plasticity, regulating synaptic dynamics on fast timescales. Although SF is known to depend on the presynaptic accumulation of Ca(2+), its precise mechanism is still under debate. Recently it has been shown that at certain central synapses SF results at least in part from the progressive saturation of an endogenous Ca(2+) buffer (Blatow et al., 2003), as proposed by Klingauf and Neher (1997). Using computer simulations, we study the magnitude of SF that can be achieved by a buffer saturation mechanism (BSM), and explore its dependence on the endogenous buffering properties. We find that a high SF magnitude can be obtained either by a global saturation of a highly mobile buffer in the entire presynaptic terminal, or a local saturation of a completely immobilized buffer. A characteristic feature of BSM in both cases is that SF magnitude depends nonmonotonically on the buffer concentration. In agreement with results of Blatow et al. (2003), we find that SF grows with increasing distance from the Ca(2+) channel cluster, and increases with increasing external Ca(2+), [Ca(2+)](ext), for small levels of [Ca(2+)](ext). We compare our modeling results with the experimental properties of SF at the crayfish neuromuscular junction, and find that the saturation of an endogenous mobile buffer can explain the observed SF magnitude and its supralinear accumulation time course. However, we show that the BSM predicts slowing of the SF decay rate in the presence of exogenous Ca(2+) buffers, contrary to experimental observations at the crayfish neuromuscular junction. Further modeling and data are required to resolve this aspect of the BSM.

Animals↗
PubMed1985

Compartmentalization of the submembrane calcium activity during calcium influx and its significance in transmitter release.

Quantitative modeling indicates that, in presynaptic terminals, the intracellular calcium concentration profile during inward calcium current is characterized by discrete peaks of calcium immediately adjacent to the calcium channels. This restriction of intracellular calcium concentration suggests a remarkably well specified intracellular architecture such that calcium, as a second messenger, may regulate particular intracellular domains with a great degree of specificity.

Animals↗
PubMed1999

Properties of a model of Ca++-dependent vesicle pool dynamics and short term synaptic depression.

We explore the properties of models of synaptic vesicle dynamics, in which synaptic depression is attributed to depletion of a pool of release-ready vesicles. Two alternative formulations of the model allow for either recruitment of vesicles from an unlimited reserve pool (vesicle state model) or for recovery of a fixed number of release sites to a release-ready state (release-site model). It is assumed that, following transmitter release, the recovery of the release-ready pool of vesicles is regulated by the intracellular free Ca(++) concentration, [Ca(++)](i). Considering the kinetics of [Ca(++)](i) after single presynaptic action potentials, we show that pool recovery can be described by two distinct kinetic components. With such a model, complex kinetic and steady-state properties of synaptic depression as found in several types of synapses can be accurately described. However, the specific assumption that enhanced recovery is proportional to [Ca(++)](i), as measured with Ca(++) indicator dyes, is not confirmed by experiments at the calyx of Held, in which [Ca(++)](i)-homeostasis was altered by adding low concentrations of the exogenous Ca(++) buffer, fura-2, to the presynaptic terminal. We conclude that synaptic depression at the calyx of Held is governed by localized, near membrane [Ca(++)](i) signals not visible to the indicator dye, or else by an altogether different mechanism. We demonstrate that, in models in which a Ca(++)-dependent process is linearly related to [Ca(++)](i), the addition of buffers has only transient but not steady-state consequences.

Action Potentials↗
PubMed2002

Immunohistochemical comparison of alpha- and beta-synuclein in adult rat central nervous system.

We investigated the immunohistochemical localization of alpha- and beta-synuclein (alphaS and betaS) in the adult rat CNS and compared the distribution of these proteins with that of synaptophysin (SYN), a well-established presynaptic marker. Anti-SYN, alphaS and betaS antibodies immunolabeled the neuropil in a punctate pattern. No SYN immunoreactivity was found in the neuronal cytoplasm. In contrast, both anti-alphaS and betaS immunostained the neuronal cytoplasm and nucleus to various extents depending on the brain region. alphaS-positive neurons were found in the olfactory bulb, deeper layers of the cerebral neocortex, substantia nigra and pontine nucleus. Immunoreactivity was most intense in neurons of the substantia nigra. betaS-positive neurons were more widely distributed throughout the CNS: more than 50% of neurons were positive for betaS in the granular cell layer of the olfactory bulb, layer IV of the cerebral cortex, CA3 of the hippocampus, basal ganglia and thalamic reticular nuclei. Moreover, there were differences among these proteins in the distribution pattern of immunoreactivity in the neuropil in some CNS regions. These findings suggest that although alphaS and betaS are concentrated in presynaptic terminals, significant amounts of these proteins are also present in the neuronal perikarya. Furthermore, the distribution of alphaS-positive neurons is similar to that of intraneuronal inclusions in alphaS transgenic animals as well as in human alpha-synucleinopathies.

Animals↗