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Biomedical subjects

M A Corner

Publications and source records attributed to M A Corner.

At least 19 recordsLinked to original sources
PubMed1996

Growth cone dynamics and activity-dependent processes in neuronal network development.

Many structural and functional properties of neuronal networks find their origin in the dynamic behavior of growth cones during development. The variation in dendritic morphologies can be traced back to random branching of growth cones. Segment length characteristics arise under random branching and steady growth cone propagation. Delayed outgrowth, as a result of competition between growth cones after splitting, is hypothesized to explain different lengths of paired terminal segments in Purkinje cells. The implications of activity-dependent neurite outgrowth were studied using an outgrowth function based on the theory of Kater et al. (1988, 1990). This theory embodies a homeostatic principle, according to which a neuron adapts its neuritic field so as to maintain a certain level bioelectric activity. It is shown that such homeostasis has many implications for neuromorphogenesis and network formation, as it may underlie phenomena such as overshoot during development, size differences among cells, differentiation between excitatory and inhibitory cells and compensatory sprouting. Finally, function-dependent regulation of development involves physiological as well as morphological variables. For instance, activity dependent regulation of ionic conductances such as to stabilize functional activity can result in a differentiation of certain neurons into, respectively, bursting and regular firing sub-types (Abbot et al., 1993; LeMasson et al., 1993). Similarly, the GABAergic phenotype comes fully to expression in hindbrain (cerebellar) and forebrain (neocortical) networks only if the level of ongoing excitatory activity during development is sufficiently high, whereas chronically intensified activity leads to a compensatory hypertrophy of inhibitory mechanisms (for review, see Corner 1994). Many of these results could only have been obtained by the use of mathematical models which allow rigorous analysis of the consequences of basic assumptions in the dynamics of neurite outgrowth. All in all, the findings further emphasize the role of spontaneous bioelectric activity during early development in neuronal network formation, the importance of which was first established in cultures of developing neural tissue.

Animals↗
PubMed1995

Implications of activity dependent neurite outgrowth for neuronal morphology and network development.

Empirical studies have demonstrated that electrical activity of the neuron can directly affect neurite outgrowth. In this paper, we study the possible implications of activity-dependent neurite outgrowth for neuronal morphology and network development, using a model in which initially disconnected cells organize themselves into a network under the influence of their intrinsic activity. A neuron is modelled as a neuritic field, the growth of which depends on its own level of activity, and neurons become connected when their fields overlap. In a purely excitatory network, we have previously demonstrated that activity-dependent outgrowth in combination with a neuronal response function with some form of firing threshold is sufficient to cause a transient overproduction (overshoot) in the number of connections or synapses. Here we show that overshoot still takes place in a network of excitatory and inhibitory cells, and can even be enhanced. With delayed development of inhibition the growth curve of the number of inhibitory connections no longer exhibits overshoot. An interesting emergent property of the model is that, solely as the result of simple outgrowth rules and cell interactions, the (dendritic) fields of the inhibitory cells tend to become smaller than those of the excitatory cells, even if both type of cells have the same outgrowth properties. Other consequences of the interactions among outgrowth, excitation and inhibition are that (i) the spatial distribution of inhibitory cells becomes important in determining the level of inhibition; (ii) pruning of connections can no longer take place if the network has grown without proper electrical activity for longer than a certain critical period; (iii) inhibitory cells, by inducing outgrowth, can help to connect different parts of a structure. Further, the model predicts that excitatory cell death will be accompanied by an increased neuritic field of surviving neurons ("compensatory sprouting"). The similarities of the model with findings in developing tissue cultures of dissociated cells are extensively discussed.

Animals↗
PubMed1994

Activity-dependent plasticity of inhibitory and excitatory amino acid transmitter systems in cultured rat cerebral cortex.

Chronic suppression of spontaneous bioelectric activity in cultures of dissociated fetal rat cerebral cortex increases neuronal cell death and results in electrophysiological changes which indicate an altered balance between excitatory and inhibitory neurotransmission in culture. To delineate whether alterations in neurotransmitter release could underlie this imbalance, we investigated the effects of chronic tetrodotoxin (TTX) treatment on the content and release of glutamate, aspartate and gamma-aminobutyric acid (GABA) in culture. Chronic TTX treatment decreased the content of all amino acids investigated. However, only GABA was decreased relative to the neuronal marker NSE (neuron-specific enolase), indicating a disproportionate loss of GABA production following chronic silencing. Depolarization-induced release of GABA, glutamate and aspartate increased about 10-fold between 7 and 21 days in control cultures. Chronic TTX treatment significantly increased the depolarization-induced release of glutamate and aspartate at 7 days in vitro relative to control levels. At all ages it caused a two-fold increase in the ratio of evoked excitatory amino acid release to that of GABA. These observations suggest that chronic silencing of developing neocortex cell cultures increases the ratio of excitatory to inhibitory synaptic activity either by differential cell death or by reduced synaptic efficiency, on which a decrease in GABA neurotransmission appears to play a major role. Since similar mechanisms may be involved in activity-dependent plasticity in vivo, these cultures provide a useful model to analyse this phenomenon at the cell biological and molecular level.

Animals↗
PubMed1993

A developmental decrease in NMDA-mediated spontaneous firing in cultured rat cerebral cortex.

In primary cultures of fetal rat cerebral cortex chronic manipulation of the level and/or pattern of bioelectric activity leads to plastic changes in bioelectric activity, opposite to those seen during the manipulation. This suggests the presence of adaptive mechanisms which regulate functional development in the neuronal network. Since NMDA receptors play an important role in early postnatal bioelectric activity and have been implicated in activity-dependent plasticity in vivo, the involvement of NMDA and non-NMDA receptors in spontaneously occurring bioelectric activity was investigated in cultured rat cerebral cortex by assaying the effects of NMDA and non-NMDA antagonists on neuronal firing. In addition, the physiological consequences of chronic suppression of bioelectric activity were investigated following development in the presence of tetrodotoxin. NMDA receptors appeared at all ages to be more crucial for spontaneous bioelectric activity than non-NMDA receptors, although their relative importance decreased during the first 3 weeks. Whereas the NMDA antagonist APV strongly reduced burst firing, the non-NMDA antagonist DNQX tended to increase burst firing slightly. Following chronic suppression of bioelectric activity, non-variable burst firing was increased, thus replicating previous findings in cerebral cortex culture grown under different conditions. The prominence of NMDA receptor activation in spontaneous bioelectric activity in early cultures suggests a role for these receptors in activity-dependent functional plasticity, as found in vivo.

2-Amino-5-phosphonovalerate↗
PubMed1992

Spontaneous firing as an epigenetic factor in brain development--physiological consequences of chronic tetrodotoxin and picrotoxin exposure on cultured rat neocortex neurons.

Functional consequences of either suppressing or intensifying spontaneous neuronal firing have been studied in developing rat cerebral cortex cultures using, respectively, tetrodotoxin (TTX) and picrotoxin (PTX) added chronically to the growth medium. Simple measures derived from the interspike interval histogram were able to powerfully discriminate between age and treatment groups. After return to control medium, most TTX-treated neurons spontaneously displayed stereotyped clustering of action potentials ('phasic' firing) which closely resembled the characteristic firing patterns seen acutely in the presence of PTX. The 'TTX-syndrome' thus suggests that GABAergic synaptic inhibition is ineffective in cortical networks grown under conditions which prevent the expression of bioelectric activity. In contrast, after return to control medium, neurons which had been partially disinhibited throughout development (by continuous exposure to PTX) had even less phasic firing than was measured in age-matched controls. Based upon these and previous findings, a two (main) factor model is put forth which can economically account for the major effects. The working hypothesis embodied in this model is that phasic neuronal discharges not only accelerate the maturation of excitatory connections within the neocortex but, even more important, are crucial for the development of adequate inhibitory synaptic transmission.

Animals↗
PubMed1992

The emergence of long-lasting transients of activity in simple neural networks.

The question was investigated whether long-lasting transients of activity, observed to occur in the intact cerebral cortex (EEG slow (delta) waves and 'K' complexes) as well as in isolated tissues cultured in vitro, can also emerge in a model network of excitatory and inhibitory cells. We show that such transients can indeed occur even if the cells do not have built-in slow kinetics. For certain parameter settings, the network is in a bistable state in which periods of increased activity (long-lasting transients) alternate with minimal activity. Transients are triggered by spontaneously firing cells ('noise'), which, rather than via a build-up of recurrent synaptic inhibition, also initiate their termination. During a transient, the network continually makes transitions from one equilibrium to another as a result of spontaneous firing until it is switched back to the quiescent state, i.e., after a variable period of time of noise-induced transitions the transient is terminated. If the network is small, activity can terminate even without inhibition. In large networks, inhibition keeps the network sensitive to spontaneously firing cells by holding it in the neighbourhood of a critical point between active and quiescent state.

Action Potentials↗
PubMed1992

Effects of spontaneous bioelectric activity and gangliosides on cell survival in vitro.

Chronic suppression of spontaneous bioelectric activity in spinal cord explants in the presence of tetrodotoxin (TTX) during network formation caused a large reduction in cell number (lowered DNA levels). The addition of gangliosides failed to protect against this cell loss. Conversely, the omission of galactose from the growth medium had no effect on DNA levels. It was concluded that the presence or absence of afferent selectivity is unlikely to require the survival of a regionally specific subpopulation of preferred dorsal root ganglion target cells. Neocortical explants also showed a large reduction in DNA levels following chronic TTX treatment, and morphometric analysis confirmed that neuronal survival was affected to the same degree. Chronic ganglioside supplementation failed to influence DNA and cell counts in either control or TTX-treated explants, but one of the added gangliosides (GD1a) stimulated extensive neuritic outgrowth in electrically silenced cultures. Particular ganglioside species, therefore, may exert a growth stimulating influence that can partially compensate for the absence of bioelectric self-stimulation during early development.

Animals↗
PubMed1992

Spike-train analysis reveals "overshoot" in developing rat prefrontal cortex function.

A multivariate analysis of spontaneous single neuron firing in the developing prefrontal cortex (PFC) of urethane anesthetized rats has been made using selected spike-train parameters. In particular, the development of modal interspike intervals closely paralleled the volumetric 'overshoot' reported earlier by us for rat PFC. Thus, the growth phase is characterized by progressively higher firing rates associated with longer modal intervals (i.e., a change from phasic to tonic firing, suggestive of increasingly effective inhibition). In contrast, the subsequent abrupt reduction in PFC volume is accompanied by the appearance of extremely short interspike intervals with no concomitant change in overall mean discharge rates ('burst' firing). This last development could be largely due to the 'pruning' of excessive excitatory synaptic contacts.

Action Potentials↗
PubMed1991

Spectral analysis of the electroencephalogram in neonatal rats chronically treated with the NMDA antagonist MK-801.

In order to study the involvement of NMDA-receptor activation in brain development, rat pups were chronically treated with the non-competitive NMDA antagonist MK-801 during the neonatal period. We recorded the cortical EEG at various vigilance states throughout the treatment period. Spectral analysis of the EEG showed reduced power in the delta (delta) frequency range (1.5-4 Hz) during quiet sleep and less power in the theta (theta) range (4-7 Hz) during REM-sleep in MK-801 animals than in controls. No significant differences were found for the total time spent in each of the different vigilance states. We conclude that chronic MK-801 treatment probably causes a developmental retardation in state-related brain activities.

Animals↗
PubMed1991

Abnormalities in the spontaneous firing patterns of cultured rat neocortical neurons after chronic exposure to picrotoxin during development in vitro.

We have used the GABA-A antagonist picrotoxin (PTX) to investigate whether chronic disinhibition, leading to intensified neuronal firing, would induce a specific pattern of physiological alterations in cultured rat neocortex cells. Overall mean spontaneous discharge rates were little affected by 1 microM PTX but firing occurred mainly as repetitive high-frequency bursts of action potentials. This "phasic" pattern contrasted with the irregular, quasi-random, firing usually seen in control units. Neurons tested in normal growth medium after prolonged exposure to 1 microM PTX showed weaker interspike interval dependencies (Markov value) than in controls, along with reduced regularity in the occurrence of bursts. Since all physiological changes were opposite in direction to those reported earlier after chronic suppression of bioelectric activity, the results support the hypothesis that endogenous synaptic and/or action potentials are important for the maturation of neocortical networks. Since experimental alterations were found only in spike-train parameters which reflect ontogenetic changes in untreated control cultures, GABAergic inhibition (by preventing neuronal discharges from becoming too intense) presumably serves to constrain the rate of development within optimal limits.

Action Potentials↗
PubMed1991

Developmental changes in B-50 (GAP-43) in primary cultures of cerebral cortex: content and phosphorylation of B-50.

The content and phosphorylation of the neuronal growth-associated protein B-50 (GAP-43) were studied in cultured neocortex as a function of normal development and development in the presence of tetrodotoxin (TTX), a blocker of bioelectric activity (BEA). The observations were correlated with previous morphological findings on neurite outgrowth and B-50 immunolocalization in the same cultures. In control cultures, the concentration of B-50 reached a maximum at 7 days in vitro (DIV) and decreased thereafter, whereas the concentration of neuron specific enolase (NSE), which was used as a neuronal reference marker, rose till 28 DIV and leveled off towards 42 DIV. The degree of basal phosphorylation of B-50 (relative to that of total protein) decreased after the first week in vitro. Stimulation of B-50 phosphorylation by phorbol ester also decreased with age in vitro, indicating that changes in B-50 phosphorylation were mainly due to changes in protein kinase C (PKC) activity. The chronic presence of TTX led to a reduced content of B-50 and NSE after 14 DIV. The basal phosphorylation of B-50 was neither affected by acute nor chronic TTX treatment. However, upon stimulation of PKC with phorbol esters, some alterations of B-50 phosphorylation were revealed in cultures grown in TTX. These biochemical observations are in line with the absence of effects of TTX on neurite outgrowth during the first 2 weeks in culture, and later effects of TTX on neuronal survival. The developmental changes in B-50 concentration and phosphorylation largely correlate with previous morphological observations on axonal outgrowth and growth cone shape in the same cultures. We suggest that B-50 phosphorylation plays an important role in transducing extracellular signals into directed neurite outgrowth.

Animals↗
PubMed1990

Development in the absence of spontaneous bioelectric activity results in increased stereotyped burst firing in cultures of dissociated cerebral cortex.

Quantitative analysis of neuronal firing patterns was used to study the effects of chronic suppression of bioelectric activity (BEA) on functional development in primary cultures of fetal rat cerebral cortex. BEA was monitored with extracellular electrodes in active control cultures or, after return to control medium, in cultures chronically silenced with tetrodotoxin (TTX) at around 7, 14, 21 and 42 days in vitro. Spike trains of single neurons lasting up to 25 min duration were analyzed using a previously published set of computer programs. In control cultures, the main developmental trends seen in a previous study could be replicated. After development in the presence of TTX, activity levels were increased at all ages, and a high incidence was found of a single firing pattern characterized by stereotyped burst firing, while showing a low minute order variability in firing rate and low dependencies between successive intervals; conversely, the incidence of variable/non-burst firing was decreased relative to untreated cultures. The former firing pattern (i.e. non-variable bursting) could also be produced through acute addition of the GABA (A)-antagonist picrotoxin to control cultures, and resembled interictal burst firing observed in models of chronic epilepsy in vivo. These similarities suggest that chronic silencing of the cultures may have resulted in a functional disinhibition of the neuronal network; such disinhibition might be related to the increased cell death which we observed with chronic TTX-treatment in the same cultures.

Action Potentials↗
PubMed1990

Spontaneous neuronal firing patterns in the occipital cortex of developing rats.

Spontaneous action potentials have been recorded in the cerebral cortex of developing rats under chloral hydrate anaesthesia. These "spike-trains" were subjected to a multivariate analysis of parameters describing different aspects of temporal patterning within each train. Three parameters which reflected clustering of action potentials in, respectively, the range of: (i) milliseconds (the modal interval, derived from the interval histograms); (ii) seconds (the mean "burst period", i.e. the time elapsing between the onset of successive clusters of relatively short intervals); and (iii) minutes (the coefficient of variation for the number of spikes in consecutive 2 min time bins) showed distinctive developmental patterns.

Action Potentials↗
PubMed1987

Spontaneous neuronal firing patterns in fetal rat cortical networks during development in vitro: a quantitative analysis.

The development of spontaneous bioelectric activity (SBA) was studied in dissociated occipital cortex cultures prepared from 19 day old rat fetuses. All cultures, recorded one per diem from 5 to 33 days in vitro (div), showed SBA. Computer analysis of 76 extracellularly recorded single unit spike trains was carried out after selection on the basis of stationarity criteria. Statistically significant developmental trends were found in (i) interspike interval dependencies and (ii) fluctuations in mean firing rate, on the order of a minute or longer. The highly dependent firing patterns, including stereotyped bursting, were present mostly in the 9-12 div group, whereas minute-to-minute fluctuations in the intensity of firing were considerably more pronounced in the oldest group (22-33 div) than in the younger cultures. In addition, firing categories defined on the basis of factor-analysis revealed that such fluctuations were almost exclusively to be found in neurons which fired in a pronounced 'burst', rather than a relatively continuous fashion. Only a few mature appearing synaptic structures were observed electron microscopically prior to 12 div, but increased steadily in number thereafter. No cultures prior to 14 div, but all cultures older than this, stained positively for the presence of glutamic acid decarboxylase. An extensive immunoreactive, putative GABAergic, network was present by three weeks in vitro.

Action Potentials↗
PubMed1987

Central neuronal responsiveness to sensory ganglion stimulation is correlated with the incidence of spontaneous bioelectric activity in developing spinal cord cultures.

In spinal cord explants co-cultured with dorsal root ganglion cells for 3-4 weeks in a (horse)serum-containing medium, the spread of ganglion-evoked action potentials from monosynaptic innervation sites ("polysynaptic excitability index") was not correlated with the incidence of neuronal "background" discharges. Moreover, chronic exposure of serum-grown cultures to tetrodotoxin (TTX) in a dose sufficient to reversibly block bioelectric activity, failed to significantly affect this index. For explants grown in a chemically defined medium (CDM) similar excitability scores were obtained only if a low level of spontaneous activity was measured. The most active preparations scored considerably higher, with intermediate values being found in the moderately active cultures. Chronic TTX-exposure in developing CDM-grown cultures reduced their excitability scores to the level found in weakly active, untreated, explants despite a normal incidence of spontaneous activity. The present study indicates that low levels of spontaneous activity in untreated explants were associated with a similar sluggishness of DRG-evoked responses as previously observed after chronic treatment with TTX. These results give additional grounds for confidence that this reduced responsiveness of spinal cord neurons to sensory input is indeed attributable to prolonged reduction of centrally generated excitation during development in vitro.

Aging↗
PubMed1987

Indications for a critical period for synapse elimination in developing rat cerebral cortex cultures.

It was observed in an earlier study that chronic tetrodotoxin (TTX) blockade of spontaneous bioelectric activity (SBA) in rat cerebral cortex cultures prevented the large-scale elimination of synapses which normally occurs during the fourth week in vitro. This prompted us to study whether the persisting high synapse density during long-term TTX-treatment would still return to the "normal' low level after restoration of SBA. Therefore, cultures grown in TTX-supplemented medium for 5 weeks were switched to control medium for an additional week prior to fixation. Electron microscopic analysis showed that the numerical synapse density remained at a high level, thus suggesting the presence of a critical period whereafter bioelectrically controlled elimination of redundant connections no longer occurs. In contrast, the mean size of synaptic structures depended only on the functional state of the tissue at the moment of fixation, being larger in TTX-silenced cultures than in bioelectrically active ones regardless of treatment during the first 5 weeks in vitro.

Animals↗