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PubMed1998

Mechanisms of generalized absence epilepsy.

Absence seizures represent bilaterally synchronous burst-firing of an ensemble of reciprocally connected neuronal populations located in the thalamus and neocortex. Recent studies demonstrate that neurons in the reticular thalamic nucleus (nRt), thalamic relay neurons (RNs), and neocortical pyramidal cells comprise a circuit that sustains the thalamocortical oscillatory burst-firing of absence seizures. Recent studies have focused on three intrinsic neuronal mechanisms that increase the likelihood of thalamocortical oscillations. The first mechanism involves T-currents elicited by activating the T-type calcium channel, which appear to trigger sustained burst-firing of thalamic neurons during absence seizures. A second intrinsic mechanism is GABA B receptors which can elicit longstanding hyperpolarization in thalamic neurons required to 'prime' T-channels for sustained burst-firing. A third mechanism involves the ability of GABA A receptors, located on nRt neurons, to mediate recurrent inhibition. Enhanced activation of GABA A receptors on nRt neurons decreases the pacemaking capacity of these cells, therefore decreasing the likelihood of generating absence seizures. Cholinergic mechanisms through modulating cortical excitability and excitatory amino acid mediated mechanisms through depolarizing thalamic neurons also play a role in absence seizures.

Animals↗

PubMed1999

Expression of synaptic proteins in the developing rat cerebellum following ionizing radiation.

Various proteins regulating neurotransmission release and synaptic vesicle exocytosis have been implicated in axonal elongation and synaptic maturation. In the present study, immunohistochemistry to the presynaptic membrane proteins syntaxin-I and synaptosomal-associated protein of 25 kDa (SNAP-25) synaptic vesicle-associated proteins synaptophysin and synapsin-I and the neuronal maturation and axonal growth-related protein GAP-43, has been carried out in the normal developing cerebellum and following a single dose of ionizing radiation (2 Gy gamma-rays) at postnatal day 1. Our aim has been to learn about the morphological and possible functional modalities that occur during the progression of neuronal connectivity in normal and abnormal development. Expression of all these proteins is associated with the arrival of afferents in the subcortical white matter and with the maturation of the internal granule cell layer and molecular layer during normal development. In addition, SNAP-25 and GAP-43 are strongly expressed in granule cells of the external granule cell layer, thus suggesting that these proteins are involved in cell elongation of granule cells. Apoptosis appears at 3 h and peaks at 6 h following ionizing radiation. Radiation-induced apoptosis in the external granule cell layer produces a transient decrease in the expression of SNAP-25 and GAP-43 in the external granule cell layer. The external granule cell layer recovers at 48 h and external granule cells of proliferating cells also express SNAP-25 and GAP-43, thus indicating that proliferating cells in this layer are equipped with proteins involved in cell elongation. Furthermore, expression of synaptophysin, synapsin-I, syntaxin-I and SNAP-25 is the same in the cerebellum of irradiated and normal rats from this time to adulthood (3 months). These results point to the likelihood that recovery of the cerebellar cortex occurs following a single exposure of ionizing radiation during postnatal development.

Aging↗

PubMedDate not supplied

Effect of developmental lead exposure on the expression of specific NMDA receptor subunit mRNAs in the hippocampus of neonatal rats by digoxigenin-labeled in situ hybridization histochemistry.

The N-methyl-D-aspartate (NMDA) receptor has an important role in learning and memory. In this study, the effects of chronic Pb exposure on NMDA receptor subunit mRNAs expression in the developing rat hippocampus were examined by digoxigenin (DIG)-labeled in situ hybridization. In Pb-exposed rats, hippocampal NR1-2a mRNA levels were significantly increased in CA1, CA4 and DG subfields at 15 days of age and CA4 and DG subfields at 20 days of age. The lead (Pb) exposure resulted in a significant increase of NR2D mRNA levels in CA1, CA2, CA4 and DG hippocampal subfields at 20 days of age. Hippocampal NR2A mRNA levels were significantly decreased in CA1, CA2, CA3 and DG subfields from 15-day-old Pb-exposed rats and CA1, CA3 and DG subfields from 20-day-old Pb-exposed rats. Hippocampal NR3A mRNA levels were also significantly decreased in CA1, CA4 and DG subfields at 15 days of age and CA1 and DG subfields at 20 days of age in Pb-exposed rats. The Pb-induced subunit specific changes in hippocampal NMDA receptor subunit mRNA expression may lead to abnormality of natural NMDA stoichiometry and interfere with the physiological function of the NMDA receptor in the development of defined neuronal connections.

Age Factors↗

PubMed1996

Labeling neural cells using adenoviral gene transfer of membrane-targeted GFP.

We describe an experimental system to visualize the soma and processes of mammalian neurons and glia in living and fixed preparations by using a recombinant adenovirus vector to transfer the jellyfish green fluorescent protein (GFP) into postmitotic neural cells both in vitro and in vivo. We have introduced several modifications of GFP that enhance its fluorescence intensity in mammalian axons and dendrites. This method should be useful for studying the dynamic processes of cell migration and the development of neuronal connections, as well as for analyzing the function of exogenous genes introduced into cells using the adenovirus vector.

Adenoviridae↗

PubMed1996

Postsynaptic elevation of calcium induces persistent depression of developing neuromuscular synapses.

Synaptic activity is known to modulate neuronal connectivity in the nervous system. At developing Xenopus neuromuscular synapses in culture, repetitive postsynaptic application of ACh near the synapse leads to immediate and persistent synaptic depression, which was shown to be caused by reduction of presynaptic evoked transmitter release. However, little depression was found when ACh was applied to the muscle 20 microns or further from the synapse. Fluorescence imaging of cytosolic Ca2+ ([Ca2+]i) showed that each ACh pulse induced a transient elevation of myocyte [Ca2+]i that spread approximately 20 microns. Local photoactivated release of Ca2+ from the caged Ca2+ chelators nitr-5 or nitrophen in the postsynaptic cell was sufficient to induce persistent synaptic depression. These results support a model in which localized Ca2+ influx into the postsynaptic myocyte initiates transsynaptic retrograde modulation of presynaptic secretion mechanisms.

Acetylcholine↗

PubMed2002

Can Eph receptors stimulate the mind?

The Eph receptors are multitalented tyrosine kinases capable of performing many tasks. The receptors together with their ligands--the ephrins--are well known to play a critical role in the initial assembly of neuronal circuits in the embryo. However, the recently discovered function of these receptors in the adult brain is now receiving significant acclaim. Three new articles show that the Eph receptors continue to be important in modifying the strength of existing neuronal connections (synapses). They do so in close association with at least one family of ion channels, the NMDA receptors.

Animals↗

PubMed1997

The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia.

Two separate theories that attempt to explain different aspects of schizophrenia have recently attracted much attention. The first, the neurodevelopmental hypothesis, postulates that deviations in early development establish a neuronal phenotype that predisposes to, or, in some versions, determines the later onset of schizophrenia. The second theory proposes that schizophrenic symptoms arise from abnormalities in neuronal connectivity. Here, we suggest that the findings from these two separate lines of inquiry can be integrated into a unitary framework: the dysplastic net hypothesis. In essence, this proposes that anatomical and physiological dysconnectivity of the adult schizophrenic brain is determined by dysplastic fetal brain development. We also indicate how abnormal connectivity between brain regions constituting large-scale neurocognitive networks is expressed in both the prepsychotic and psychotic phases of schizophrenia, and we examine possible risk factors (genetic and environmental) for dysplastic formation of these networks.

Adult↗

PubMed1998

Molecular regulators involved in vertebrate eye development.

Development of the eye can be subdivided into three phases. The first phase is the formation of the major structures of the eye by the processes of induction and regional specification. The second is the maturation of these structures to form the functional eye, and the third phase is the formation of neuronal connections between retina and the optic tectum. These processes are tightly regulated by signalling cascades that direct axonal outgrowth, cellular proliferation and differentiation. Some members of these signalling cascades have been identified in recent studies. These include secreted factors which transmit signals extracellularly, and receptors and transcription factors which are members of intracellular signalling pathways that respond to extracellular signals. This review summarizes the recent research that has implicated these factors in playing a role in eye development on the basis of functional or expression criteria.

Animals↗

PubMed1996

Cell adhesion molecules and the transition from short- to long-term memory.

Training chicks on a one-trial passive task results in a cascade of molecular and cellular processes in two forebrain regions, culminating within 60-90 min in post-translational glycosylation of synaptic membrane proteins and expression of immediate early genes c-fos and c-jun. We have found a second window of vulnerability of memory to the protein synthesis inhibitor anisomycin, 4 h downstream of training. By 5.5 h post-training this window closes, to be replaced by a window of sensitivity to blockade of glycoprotein synthesis, presumably representing post-translational modification of the newly synthesised proteins. Amongst the pre- and post-synaptic membrane glycoproteins involved it both first and second time windows are the cell adhesion molecules, L1 (at both times) and NCAM (at the later). Molecular dissection of the external membrane domains of L1 distinguishes between a requirement for the IgG domain at the early time, the fibronectin-like domain at the later. The second time window only occurs if the animal is trained on a stimulus strong enough to be remembered for a long period. Weak memories do not persist beyond 6-8 h and the second wave of glycoprotein synthesis does not occur. Thus the second wave may represent the molecular processes required for the alterations in synaptic configuration, by way of the adhesion molecules amongst others, required for the morphological changes in neuronal connectivity hypothesised to encode memory.

Animals↗

PubMedDate not supplied

TrkA antagonists decrease NGF-induced ChAT activity in vitro and modulate cholinergic synaptic number in vivo.

Cholinergic neurons are known to respond in vivo to the administration of nerve growth factor (NGF) by a prominent and selective increase of choline acetyl transferase activity and by cholinergic synaptogenesis in the rat brain. By using a synthetic TrkA antagonist we demonstrated that endogenously produced NGF is involved in the continual re-modeling of cholinergic neuronal connections during adulthood, acting through TrkA receptors.

Acetylcholine↗

PubMed1992

Synaptic reorganization in developing and adult nervous systems.

Evidence is accumulating that synapse reorganization already starts during development, soon after first synapses appear. Although remodeling continues throughout ontogenesis, there are apparently (critical) periods which are characterized by enhanced synaptic reorganization. In certain parts of the peripheral and central nervous system, synapses may undergo remodeling which leads to changes in their transmission efficiency or complete elimination of the synaptic junctions, even in adulthood. Synaptic reorganization includes progressive and regressive changes on branches of dendritic and/or axonal processes that accompany the formation and elimination of synapses. Three modes of elimination are presently known: Physiological cell death of synaptically connected neurons is involved, especially during certain developmental periods, during hormonally induced metamorphosis and in the olfactory bulb. Synaptic disconnection ("stripping") and lysosomal degradation predominantly of presynaptic elements occur under different conditions. In order to undergo plastic changes, neurons seem to respond to exogenous or intrinsic factors such as lesions (partial deafferentation and axotomy), long-lasting changes in neuronal activity (e.g. drug application and sensory deprivation), hormonal influences (e.g. sexual hormones) or learning conditions.

Aging↗

PubMed2000

Topographic mapping: organising by repulsion and competition?

The establishment of topographic maps of neuronal connections is believed to involve graded repulsion mediated by EphA receptors and ephrin-A ligands. Gene knockouts show that ephrin-A ligands do indeed have a crucial role in mapping, and that mechanisms in addition to graded repulsion must also be at work.

Animals↗

PubMed1994

Activity-dependent modulation of developing neuromuscular synapses.

Spontaneous and impulse-evoked synaptic currents were observed immediately following nerve-muscle contact in Xenopus cell cultures. The functional significance of this early synaptic activity was examined. Stimulation of pre- and/or post-synaptic cells was found to exert immediate and persistent effects on the efficacy of synaptic transmission. Exogenous application of calcitonin gene-related peptide (CGRP) and neurotrophins, factors that may be coreleased with ACh in activity-dependent manner at the developing neuromuscular junctions, also modulate either the postsynaptic ACh response or presynaptic ACh release. These results underscore the plasticity of developing neuromuscular synapses and suggest a complex interplay between electrical activity and chemical factors during the formation and maturation of neuronal connections.

Acetylcholine↗

PubMed2005

Lateral interactions in the visual cortex of patients with schizophrenia and bipolar disorder.

BACKGROUND: Schizophrenia is associated with perceptual organization deficits and abnormal neuronal connectivity has been described in early visual areas. The purpose of this study was to investigate the functional integrity of lateral connections in early visual areas of patients with schizophrenia and type I bipolar disorder with a history of psychosis. METHOD: Twenty-four out-patients with schizophrenia, 22 out-patients with bipolar disorder, and 20 healthy control subjects participated in the study. Using a computer-assisted psychophysical test, contrast thresholds were measured for centrally presented target stimuli (Gabor patches), which were surrounded by two collinear flankers. Target-to-flanker distances were 0, 1, 2, 3, 4, 6, 9 and 122. Psychophysical measures were contrast threshold changes at each target-to-flanker distance compared with baseline thresholds determined for isolated targets with no flankers. Clinical measures included IQ, positive, negative, and depressive symptoms. Results. In patients with schizophrenia, flankers did not facilitate contrast detection for target stimuli at 2-6 lambda distances compared to controls [effect size (Cohen's d): 1.25-1.42]. The inhibitory effect of flankers (0 and 1lambda) and contrast thresholds in the absence of flankers were spared. Patients with bipolar disorder did not differ from the controls. Medicated and non-medicated patients displayed similar performances. Positive and negative symptoms and depression did not correlate with contrast threshold values. CONCLUSIONS: Excitatory lateral connections in early visual cortex are specifically impaired in patients with schizophrenia, which may contribute to perceptual disorders such as unclear seeing, partial or skewed sight, disrupted rectilinearity, and abnormal figure-ground segregation.

Adult↗

PubMed2006

Précis of principles of brain evolution.

Brain evolution is a complex weave of species similarities and differences, bound by diverse rules and principles. This book is a detailed examination of these principles, using data from a wide array of vertebrates but minimizing technical details and terminology. It is written for advanced undergraduates, graduate students, and more senior scientists who already know something about "the brain," but want a deeper understanding of how diverse brains evolved. The book's central theme is that evolutionary changes in absolute brain size tend to correlate with many other aspects of brain structure and function, including the proportional size of individual brain regions, their complexity, and their neuronal connections. To explain these correlations, the book delves into rules of brain development and asks how changes in brain structure impact function and behavior. Two chapters focus specifically on how mammal brains diverged from other brains and how Homo sapiens evolved a very large and "special" brain.

Animals↗

PubMed2003

Subacute sclerosing panencephalitis presenting with unilateral periodic myoclonic jerks.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a rare complication of measles virus infection. The disease is characterized by behavioural abnormalities, intellectual deterioration, motor weakness, and generalized myoclonic jerks progressing to coma and death in one to two years in 80% of the cases. The myoclonic jerks are associated with characteristic generalized slow periodic complexes on electroencephalography (EEG). The symptoms and signs of SSPE are frequently quite variable. The clinical course is equally variable and difficult to predict. The characteristic periodic myoclonus can rarely occur unilaterally particularly in the early stages of the disease. As well, the periodic EEG complexes have been reported unilaterally in up to 3% of cases. CASE REPORT: A 12-year-old boy, who was seen at a later stage with atypical manifestation of myoclonic body jerks confined entirely unilaterally, combined with contralateral periodic EEG complexes. One could assume clinically that the more diseased hemisphere was responsible for generating the jerks. However, brain magnetic resonance imaging revealed asymmetric hemispheric changes suggesting that the less neurologically damaged hemisphere is responsible for generating the unilateral myoclonic jerks. This has led to the interpretation that the more severely damaged hemisphere has lost the neuronal connectivity required to generate these periodic myoclonic jerks. CONCLUSIONS: Subacute sclerosing panencephalitis may have asymmetric hemispheric involvement, not only early, but also in the advanced stages of the disease, which can result in unilateral periodic myoclonic jerks.

Child↗

PubMed2003

Melanopsin forms a functional short-wavelength photopigment.

Recently, melanopsin has emerged as the leading candidate for the elusive photopigment of the mammalian circadian system. This novel opsin-like protein is expressed in retinal ganglion cells that form the retinohypothalamic tract, a neuronal connection between the retina and the suprachiasmatic nucleus. These hypothalamic structures contain the circadian pacemaker, which generates daily rhythms in physiology and behavior. In mammals, proper synchronization of these rhythms to the environmental light-dark cycle requires retinal input. Surprisingly, rod and cone photoreceptors are not required. Instead, the melanopsin-containing ganglion cells are intrinsically sensitive to light, perhaps responding via a melanopsin-based signaling pathway. To test this hypothesis, we have characterized melanopsin following heterologous expression in COS cells. We found that melanopsin absorbed maximally at 424 nm after reconstitution with 11-cis-retinal. Furthermore, melanopsin activated the photoreceptor G-protein, transducin, in a light-dependent manner. In agreement with the measured absorbance spectrum, melanopsin was most efficiently excited by blue light (420-440 nm). In contrast, published action spectra suggest that the photopigment underlying the intrinsic light sensitivity of SCN-projecting RGCs has an absorption maximum near 484 nm. In summary, our experiments constitute the first direct demonstration that melanopsin forms a photopigment capable of activating a G-protein, but its spectral properties are not consistent with the action spectrum for circadian entrainment.

Amino Acid Sequence↗

PubMed2002

Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in cirrhosis and role in the pathogenesis of hepatic encephalopathy.

In hepatic encephalopathy, a progressive and diffuse impairment in brain function is associated with gradual alterations that can be detected by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS). In some patients, a variety of movement disorders suggestive of extrapyramidal impairment points toward basal ganglia (BG) alterations. Accordingly, (i) hyperintensities at MRI predominant in the pallidum, an important region of BG involved in the motor control, (ii) redistribution of cerebral blood flow from cortical areas to BG structures observed using positron emission tomography studies, and (iii) the preferential pallidal location of Alzheimer astrocytosis, all support this hypothesis. In most clinical studies, little if any correlations have been found between cerebral hyperintensities and neurological manifestations. The application of a test designed to evaluate patients with Parkinson's disease (where extrapyramidal signs are typical) showed significant clinical correlations both with pallidal hyperintensity and with choline/creatine ratio at 1H MRS in BG structures. Because of complex neuronal connections between BG and many cortical areas, BG dysfunction may influence the neurocognitive manifestations of hepatic encephalopathy. Similarities between chronic Mn intoxication and cirrhosis suggest common pathophysiological mechanisms including altered dopaminergic neurotransmission, although information in chronic liver failure is limited. Clinical observations are presented regarding the evolution of parkinsonian signs in various situations.

Basal Ganglia↗