Exploring the functional role of monoaminergic neurotransmission. A method for exploring neurotransmitter dysfunction in psychiatric disorders.
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Animals↗
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Results for “synaptic dysfunction”
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Down-regulation of post-synaptic serotonin receptors as a mechanism for clomipramine-induced anorgasmia.
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Animals↗
Ischemia and lesion induced imbalances in cortical function.
Cortical structures are often critically affected by ischemic and traumatic lesions which may cause transient or permanent functional disturbances. These disorders consist of changes in the membrane properties of single cells and alterations in synaptic network interactions within and between cortical areas including large-scale reorganizations in the representation of the peripheral input. Prominent functional modifications consisting of massive membrane depolarizations, suppression of intracortical inhibitory synaptic mechanisms and enhancement of excitatory synaptic transmission can be observed within a few minutes following the onset of cortical hypoxia or ischemia and probably represent the trigger signals for the induction of neuronal hyperexcitability, irreversible cellular dysfunction and cell death. Pharmacological manipulation of these early events may therefore be the most effective approach to control ischemia and lesion induced disturbances and to attenuate long-term neurological deficits. The complexity of secondary structural and functional alterations in cortical and subcortical structures demands an early and powerful intervention before neuronal damage expands to intact regions. The unsatisfactory clinical experience with calcium and N-methyl-D-aspartate antagonists suggests that this result might be achieved with compounds that show a broad spectrum of actions at different ligand-activated receptors, voltage-dependent channels and that also act at the vascular system. Whether the same therapy strategies developed for the treatment of ischemic injury in the adult brain may be applied for the immature cortex is questionable, since young cortical networks with a high degree of synaptic plasticity reveal a different response pattern to hypoxic and ischemic insults. Age-dependent molecular biological, morphological and physiological parameters contribute to an enhanced susceptibility of the immature brain to these noxae during early ontogenesis and have to be investigated in more detail for the development of adequate clinical therapy.
Adult↗
The heroic age of neurophysiology.
Building on 19th- and early 20th-century conceptualizations--the synapse, the cellular nature of neuronal structure, the electrical basis of neural impulses--the heroic age, starting around World War I, set the stage for molecular definition of neuromuscular transmission. Without targeting specific diseases, the work took us to the verge of controlling some of humankind's cruelest dysfunctions.
History, 19th Century↗
Electron microscopic analysis of cortical biopsies in patients with traumatic brain injuries and dysfunction of neurobehavioural system.
Cortical biopsies of eight patients with craniocerebral trauma complicated with subdural or epidural hematoma were examined with the transmission electron microscope. The patients showed post-traumatic neurobehavioural disorders and moderate or severe vasogenic brain edema. The capillary wall displayed increased vacuolar and vesicular endothelial transport, basement membrane thickening and vacuolization and swollen astrocytic end-feet. Pericapillary and parenchymatous hemorrhages were also observed. The extracellular space appeared considerably enlarged with presence of proteinaceous hematogenous edema fluid and fibrinous organization. Pyramidal and non-pyramidal neurons showed intracellular edema featured by irregular enlargement of rough endoplasmic reticulum, nuclear envelope and Golgi apparatus. The myelinated axons exhibited clear or black type axoplasmic degeneration, varicose fiber swelling, myelin sheath distortion, formation of myelin ovoids and increased amount of oligodendroglial ad-axonal layer. The dendrites also showed clear or dark and beaded shape degeneration. Synaptic degeneration was characterized by swollen and shrunken pre- and postsynaptic endings, clumping, enlargement and depletion of synaptic vesicles, synaptic membrane complex disassembly and detachment of glial ensheathment. Perivascular and perineuronal astrocytes appeared remarkably swollen. Phagocytic astrocytes were also found. Oligodendrocytes displayed hydropic and reactive changes. Reactive oligodendrocytes induced myelinolysis. The brain barrier dysfunction, the vasogenic and cytotoxic edema and the subsequent neuronal and neuroglial cell reactive and degeneration processes might represent the morphological substrate responsible for the post-traumatic neurobehavioural disorders.
Adolescent↗
Interictal spikes in focal epileptogenesis.
Interictal electroencephalography (EEG) potentials in focal epilepsies are sustained by synchronous paroxysmal membrane depolarization generated by assemblies of hyperexcitable neurons. It is currently believed that interictal spiking sets a condition that preludes to the onset of an ictal discharge. Such an assumption is based on little experimental evidence. Human pre-surgical studies and recordings in chronic and acute models of focal epilepsy showed that: (i) interictal spikes (IS) and ictal discharges are generated by different populations of neuron through different cellular and network mechanisms; (ii) the cortical region that generates IS (irritative area) does not coincide with the ictal-onset area; (iii) IS frequency does not increase before a seizure and is enhanced just after an ictal event; (iv) spike suppression is found to herald ictal discharges; and (v) enhancement of interictal spiking suppresses ictal events. Several experimental evidences indicate that the highly synchronous cellular discharge associated with an IS is generated by a multitude of mechanisms involving synaptic and non-synaptic communication between neurons. The synchronized neuronal discharge associated with a single IS induces and is followed by a profound and prolonged refractory period sustained by inhibitory potentials and by activity-dependent changes in the ionic composition of the extracellular space. Post-spike depression may be responsible for pacing interictal spiking periodicity commonly observed in both animal models and human focal epilepsies. It is proposed that the strong after-inhibition produced by IS protects against the occurrence of ictal discharges by maintaining a low level of excitation in a general condition of hyperexcitability determined by the primary epileptogenic dysfunction.
Action Potentials↗
Mitochondrial dysfunction as a cause of optic neuropathies.
Mitochondria are increasingly recognized as central players in the life and death of cells and especially of neurons. The energy-dependence of retinal ganglion cells (RGC) and their axons, which form the optic nerve, is singularly skewed. In fact, while mitochondria are very abundant in the initial, unmyelinated part of the axons anterior to the lamina cribrosa, their number suddenly decreases as the myelin sheath begins more posteriorly. The vascular system also presents different blood-brain barrier properties anterior and posterior to the lamina, possibly reflecting the different metabolic needs of the optic nerve head (unmyelinated) and of the retrobulbar optic nerve (myelinated). Mitochondrial biogenesis occurs within the cellular somata of RGC in the retina. It needs the coordinated interaction of nuclear and mitochondrial genomes. Mitochondria are then transported down the axons and distributed where they are needed. These locations are along the unmyelinated portion of the nerve, under the nodes of Ranvier in the retrobulbar nerve, and at the synaptic terminals. Efficient transportation of mitochondria depends on multiple factors, including their own energy production, the integrity of the cytoskeleton and its protein components (tubulin, etc.), and adequate myelination of the axons. Any dysfunction of these systems may be of pathological relevance for optic neuropathies with primary or secondary involvement of mitochondria. Leber's hereditary optic neuropathy (LHON) is the paradigm of mitochondrial optic neuropathies where a primary role for mitochondrial dysfunction is certified by maternal inheritance and association with specific mutations in the mitochondrial DNA (mtDNA). Clinical phenocopies of this pathology are represented by the wide array of optic neuropathies associated with vitamin depletion, toxic exposures, alcohol and tobacco abuse, and use of certain drugs. Moreover, the recent identification of mutations in the nuclear gene OPA1 as the causative factor in dominant optic atrophy (DOA, Kjer's type) brought the unexpected finding that this gene encodes for a mitochondrial protein, suggesting that DOA and LHON may be linked by similar pathogenesis. Polymorphisms in this very same gene may be associated with normal tension glaucoma (NTG), which might be considered a genetically determined optic neuropathy that again shows similarities with both LHON and DOA. Exciting new developments come from first examples of mitochondrial optic neuropathies in animal models that are genetically determined or are the result of ingenious engineering of mitochondrial gene expression, or from biochemical manipulations of the respiratory complexes. Even more exciting is the first successful attempt to correct the LHON-related complex I dysfunction by the allotopic nuclear expression of the recoded mitochondrial gene. There is hope that the genetic complexities, biochemical dysfunctions, and integrated anatomical-physiological cellular relationships will soon be precisely delineated and that promising therapeutic and prophylactic strategies will be proposed.
Animals↗
Fenfluramine hydrochloride treatment of parkinsonism.
The oral administration of fenfluramine hydrochloride, which acts centrally to augment serotonin-mediated synaptic function, did not alter extrapyramidal signs in either untreated or levodopa-treated parkinsolian patients. These results support the contention that biochemical indices of serotonergic dysfunction in Parkinson disease do not reflect a critical role for serotonin-containing neural systems in the pathophysiology of parkinsonism and that serotonin-active drugs afford no significant therapeutic benefit to patients with this disorder.
Aged↗
Ammonia and disinhibition in cat motor cortex by ammonium acetate, monofluoroacetate and insulin-induced hypoglycemia.
Ammonia intoxication abolished the suppression of action potential generation by cortical postsynaptic inhibition due to the inactivation of neuronal Cl- extrusion. The disinhibition by ammonia intoxication occurred when ammonia concentrations in the cerebral cortex were increased to 320% of normal. Fluoroacetate poisoning and insulin-induced hypoglycemia, which are known to increase ammonia concentrations in the CNS and previously have been shown to inactivate Cl- extrusion in spinal motoneurons, abolished the suppression of action potential generation by cortical postsynaptic inhibition like ammonia intoxication. This disinhibition occurred at unchanged cerebral ammonia concentrations. The effect of fluoroacetate and insulin induced hypoglycemia on cortical postsynaptic inhibition is either due to a direct, i.e. not ammonia mediated, inactivation of neuronal Cl- extrusion or due to a disturbance of the synaptic mechanisms mediated by the transmitter of cortical inhibition, GABA. Toxic-metabolic encephalopathies which increase cerebral ammonia concentrations beyond 320% of normal may produce a dysfunction of the CNS due to inactivation of neuronal Cl- extrusion leading to ineffective cortical inhibition. However, in fluoroacetate poisoning and insulin-induced hypoglycemia increased ammonia concentrations in the CNS have only a secondary role in initiating a dysfunction of the CNS since disinhibition occurs before ammonia concentrations increase.
Acetates↗
The problem of assessing effective neuroprotection in experimental cerebral ischemia.
In animal models of global and focal ischemia neuroprotection is typically determined by quantifying the degree of cell loss or reduction in infarct volume shortly after the ischemic insult. These methods are unable to reliably detect more subtle forms of neuronal death and dysfunction that arise from injury to non-homogeneous cell populations (e.g. hilar and striatal neurons), or to dendrites (e.g. loss of structural proteins or decreased synaptic transmission). It is argued that this type of covert injury contributes to a wide range of functional impairments (e.g. decreased working memory, altered field potentials, loss of forelimb dexterity) that are rarely used as outcome measures in experimental studies even though they are of paramount importance clinically. The limitations of a purely histological approach in assessing neuroprotection are clearly illustrated using examples of protective drug therapies, mild hypothermia and ischemic preconditioning. An alternative strategy that incorporates behavioural, electrophysiological and histological endpoints is put forth as a more powerful method for gauging neuroprotection. The strength of this approach will be increased if these assessments are performed on the same animals. By incorporating functional measures and longer postischemic survival into their experimental protocols, investigators will increase the validity of their models and hopefully reduce the likelihood of advancing ineffective therapies into costly clinical trials.
Animals↗
Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport.
The two pathological hallmarks of Alzheimer's disease, amyloid plaques and neurofibrillary tangles, involve two apparently unrelated proteins, the amyloid precursor protein (APP) and Tau. Although it is known that aberrant processing of APP is associated with Alzheimer's disease, the definitive role of APP in neurons is not yet clear. Tau regulates microtubule stabilization and assembly in axons and is, thus, an essential component of the microtubule-associated organelle transport machinery. Although several groups have reported physical interaction between APP and Tau, and induction of Tau phosphorylation by APP and beta-amyloid peptide, the functional connection between APP and Tau is unclear. To explore the possibility that the functions of these two proteins may somehow converge on the same cellular process, we overexpressed APPL, the Drosophila homologue of APP, along with Tau in Drosophila neurons. Panneural coexpression of APPL and Tau resulted in adults that, upon eclosion, failed to expand wings and harden the cuticle, which is suggestive of neuroendocrine dysfunction. We analyzed axonal transport when Tau and APPL were coexpressed and found that transport of axonal cargo was disrupted, as evidenced by increased retention of synaptic proteins in axons and scarcity of neuropeptide-containing vesicles in the distal processes of peptidergic neurons. In an independent approach, we demonstrated genetic interaction and phenotypic similarity between APPL overexpression and mutations in the Kinesin heavy chain (Khc) gene, the product of which is a motor for anterograde vesicle trafficking.
Amyloid beta-Protein Precursor↗
The neurodegeneration sequence in prion diseases: evidence from functional, morphological and ultrastructural studies of the GABAergic system.
Loss of the GABAergic system of neurons has been reported to be the first detectable neuropathological change in prion diseases, which features the accumulation of an aberrant isoform of the prion protein (PrP(Sc)). To determine the timing of GABAergic system dysfunction and degeneration and its relationship to PrP(Sc) accumulation during the course of prion disease in Syrian hamsters, we applied 3 approaches: i) quantifying GABA-immunopositive neurons and their processes by light and electron microscopy to test for selective loss; ii) measuring evoked [3H]-GABA release from synaptosomes to test for functional abnormalities; and iii) determining the kinetics of PrP(Sc) accumulation in subcellular fractions to correlate it with GABAergic dysfunction. At the terminal stages of disease, we found a significant increase in the number of GABA-positive and -negative presynaptic boutons with abnormally aggregated synaptic vesicles. At the same stage, we also found an equal degree of GABA-immunopositive and -immunonegative presynaptic bouton loss. In contrast, GABA-positive neocortical cell bodies increased, based on stereologic estimates in the terminal stage of scrapie. In the context of these abnormalities, evoked release of [3H]-GABA from cortical and thalamic synaptosomes was significantly decreased, which correlated well with the accumulation of PrP(Sc) in synaptosomes and cell membrane fractions.
Animals↗
Persistent phosphorylation of synaptic proteins following middle cerebral artery occlusion.
Transient cerebral ischemia following 1 to 2 hours of middle cerebral artery occlusion (MCAO) in the rat leads to infarction, which can be diminished by synaptic transmission modulators, implying aberrant cell signaling in the pathogenetic process. The authors report here changes in the levels of tyrosine phosphorylated proteins (PTyr) and calcium calmodulin kinase II (CaMKII) phosphorylation of Thr 286, in synaptosomal, particulate, and cytosolic fractions of different cortical areas following 1 or 2 hours of MCAO, or 2 hours of MCAO followed by 2 hours of reperfusion. At the end of 2-hour MCAO, PTyr, and in particular the pp180, indicative of NR2A/B subunit, increased in the synaptosomal fraction in less ischemic areas while it decreased in more severe ischemic regions. During reperfusion, phosphorylation increased at least 2-fold in all reperfused areas. During 2 hours of MCAO, the phosphorylation of CaMKII increased 8- to 10-fold in the synaptosomal fraction in all ischemic brain regions. During reperfusion, the phospho-CaMKII levels remained elevated by approximately 300% compared with the contralateral hemisphere (control). There was no increase in phospho-CaMKII in the cytosolic fraction at any time during or following ischemia in any of the brain regions examined. The authors conclude that both tyrosine kinase coupled pathways, as well as CaMKII-mediated cellular processes associated with synaptic activity, are strongly activated during and particularly following MCAO. These results support the hypothesis that aberrant cell signaling may contribute to ischemic cell death and dysfunction, and that selective modulators of cell signaling may be targets for pharmacological intervention against ischemic brain damage.
Animals↗
Withanoside IV and its active metabolite, sominone, attenuate Abeta(25-35)-induced neurodegeneration.
At the present, medication of dementia is limited to symptomatic treatments such as the use of cholinesterase inhibitors. To cure dementia completely, that is regaining neuronal function, reconstruction of neuronal networks is necessary. Therefore, we have been exploring antidementia drugs based on reconstructing neuronal networks in the damaged brain and found that withanoside IV (a constituent of Ashwagandha; the root of Withania somnifera) induced neurite outgrowth in cultured rat cortical neurons. Oral administration of withanoside IV (10 micromol/kg/day) significantly improved memory deficits in Abeta(25-35)-injected (25 nmol, i.c.v.) mice and prevented loss of axons, dendrites, and synapses. Sominone, an aglycone of withanoside IV, was identified as the main metabolite after oral administration of withanoside IV. Sominone (1 microM) induced axonal and dendritic regeneration and synaptic reconstruction significantly in cultured rat cortical neurons damaged by 10 microM Abeta(25-35). These data suggest that orally administrated withanoside IV may ameliorate neuronal dysfunction in Alzheimer's disease and that the active principle after metabolism is sominone.
Amyloid beta-Peptides↗
Distally directed dendrotoxicity induced by kainic Acid in hippocampal interneurons of green fluorescent protein-expressing transgenic mice.
Excitotoxicity, resulting from the excessive release of glutamate, is thought to contribute to a variety of neurological disorders, including epilepsy. Excitotoxic damage to dendrites, i.e., dendrotoxicity, is often characterized by the formation of large dendritic swellings, or "beads." Here, we show that hippocampal interneurons that express the neuropeptide somatostatin are highly vulnerable to the excitotoxic effects of the ionotropic glutamate receptor agonist kainate. Brief, focal iontophoretic application of kainate rapidly induced bead formation in dendrites of somatostatinergic interneurons that express green fluorescent protein (GFP) from mice of the transgenic line GIN (GFP-expressing inhibitory neurons). Surprisingly, beads often did not form at the site of kainate application or even in the dendritic segment to which kainate was applied; instead, dendritic beading occurred more distally, often encompassing all branches distal to the application site. We have termed this phenomena, "distally directed dendrotoxicity." Distally directed beading was induced regardless of the branch order of the site of application and was found to be dependent on activation of voltage-gated sodium channels. Subsequent to induction, distally directed beading would reverse in most cells; in other cells, however, beading irreversibly invaded proximal dendritic segments and gradually encompassed the entire dendritic tree. These results demonstrate that distal dendritic segments are highly vulnerable to excitotoxic injury and imply that excessive excitatory activity originating in one synaptic pathway can impact synapses at more distal dendritic segments of the same neuron. The discovery of this phenomenon will likely be important in understanding interneuronal dysfunction following excitotoxic injury.
Animals↗
Changes in synapses and axons demonstrated by synaptophysin immunohistochemistry following spinal cord compression trauma in the rat and mouse.
OBJECTIVE AND METHODS: To evaluate synaptic changes using synaptophysin immunohistochemstry in rat and mouse, which spinal cords were subjected to graded compression trauma at the level of Th8-9. RESULTS: Normal animals showed numerous fine dots of synaptophysin immunoreactivity in the gray matter. An increase in synaptophysin immunoreactivity was observed in the neuropil and synapses at the surface of motor neurons of the anterior horns in the Th8-9 segments lost immunoreactivity at 4-hour point after trauma. The immunoreactive synapses reappeared around motor neurons at 9-day point. Unexpected accumulation of synaptophysin immunoreactivity occurred in injured axons of the white matter of the compressed spinal cord. CONCLUSION: Synaptic changes were important components of secondary injuries in spinal cord trauma. Loss of synapses on motor neurons may be one of the factors causing motor dysfunction of hind limbs and formation of new synapses may play an important role in recovery of motor function. Synaptophysin immunohistochemistry is also a good tool for studies of axonal swellings in spinal cord injuries.
Animals↗
[Yawning. Physiopathology and neuropharmacology].
Yawning is a common physiological phenomenon, induced by hunger, sleepiness or impersonation. Its behavioral aim seems to be an effort to vigilance. There are numerous pathological reasons explaining yawning, as for example global (infectious, metabolic and toxical) or focal neurological diseases. The modification of yawning in pathology where a dopaminergic dysfunction is to be found, as well as some data of animal experimentation, support when it takes place the dopaminergic system's implication. The pre-synaptical receptor's role had been suggested for a long time but actually yawning seems to be linked with a D1-D2 cooperation. The cholinergic system probably control a final effective pathway. We also imply the peptidergic, serotoninergic, androgine and opiace systems. If the localization of a putative center of yawning is impossible, the nigrostriatal dopaminergic pathway, the paraventricular nucleus of hypothalamus and the pituitary gland play a major role. Yawning can be used as a functioning index of the dopaminergic system in vivo in the human being.
Animals↗
Anatomical and functional recovery by embryonic stem cell-derived neural tissue of a mouse model of brain damage.
We have treated undifferentiated mouse embryonic stem (ES) cells with all-trans retinoic acid (RA) to induce differentiation in vitro into neuron-like cells with good cell viability for use as a graft. Furthermore, we asked whether the RA-induced neuron-like cells restored neurological dysfunction. To this end, the cells were transplanted into right hemiplegia model of mice, developed by a cryogenic injury of motor cortex. Motor function of the recipients was gradually improved, whereas little improvement was observed in control mice. The lesion showed clustering of mature and almost mature neuron-like cells in mice transplanted with the RA-treated cells. The grafted cells had synaptic vesicles. This finding may suggest their maturation and synaptic connection in the recipient brain. Even though further study is necessary to elucidate molecular and cellular mechanisms responsible for the functional recovery, we consider that the ES cells may have advantage for use as a donor source in various neurological disorders including motor dysfunction.
Animals↗