Search PubMed⌕ Search

Biomedical subjects

A Kirkwood

Publications and source records attributed to A Kirkwood.

At least 19 recordsLinked to original sources
PubMed1999

BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex.

Maturation of the visual cortex is influenced by visual experience during an early postnatal period. The factors that regulate such a critical period remain unclear. We examined the maturation and plasticity of the visual cortex in transgenic mice in which the postnatal rise of brain-derived neurotrophic factor (BDNF) was accelerated. In these mice, the maturation of GABAergic innervation and inhibition was accelerated. Furthermore, the age-dependent decline of cortical long-term potentiation induced by white matter stimulation, a form of synaptic plasticity sensitive to cortical inhibition, occurred earlier. Finally, transgenic mice showed a precocious development of visual acuity and an earlier termination of the critical period for ocular dominance plasticity. We propose that BDNF promotes the maturation of cortical inhibition during early postnatal life, thereby regulating the critical period for visual cortical plasticity.

Age Factors↗
PubMed1999

Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine.

In a slice preparation of rat visual cortex, we discovered that paired-pulse stimulation (PPS) elicits a form of homosynaptic long-term depression (LTD) in the superficial layers when carbachol (CCh) or norepinephrine (NE) is applied concurrently. PPS by itself, or CCh and NE in the absence of synaptic stimulation, produced no lasting change. The LTD induced by PPS in the presence of NE or CCh is of comparable magnitude with that obtained with prolonged low-frequency stimulation (LFS) but requires far fewer stimulation pulses (40 vs 900). The cholinergic facilitation of LTD was blocked by atropine and pirenzepine, suggesting involvement of M1 receptors. The noradrenergic facilitation of LTD was blocked by urapidil and was mimicked by methoxamine, suggesting involvement of alpha1 receptors. beta receptor agonists and antagonists were without effect. Induction of LTD by PPS was inhibited by NMDA receptor blockers (completely in the case of NE; partially in the case of CCh), suggesting that one action of the modulators is to control the gain of NMDA receptor-dependent homosynaptic LTD in visual cortex. We propose that this is a mechanism by which cholinergic and noradrenergic inputs to the neocortex modulate naturally occurring receptive field plasticity.

Acetylcholine↗
PubMed1997

Age-dependent decrease of synaptic plasticity in the neocortex of alphaCaMKII mutant mice.

Synaptic long-term potentiation (LTP) and long-term depression (LTD) were studied in the visual cortex of mutant mice lacking alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII). In adult mutants, little LTD or LTP could be elicited using standard conditioning protocols. However, substantial LTD and LTP were induced in 4- to 5-week-old mutants. Thus, the reduction in cortical plasticity in alphaCaMKII (-/-) mice is conditional, with the relevant condition being postnatal age.

Aging↗
PubMed1996

Decision time.

Explore the source record for details and available documents.

Aged↗
PubMed1996

Experience-dependent modification of synaptic plasticity in visual cortex.

In many regions of the cerebral cortex, Ca2+ influx through NMDA (N-methyl-D-aspartate) sensitive glutamate receptors (NMDA receptors) can trigger two forms of synaptic plasticity: long-term depression (LTD) and long-term potentiation (LTP). LTD is induced by low levels of postsynaptic NMDA-receptor activation, for instance in response to low-frequency stimulation, whereas LTP is induced by the stronger activation that occurs following high-frequency stimulation. Theoretical studies have shown that the properties of synaptic LTD and LTP can account for many aspects of experience-dependent plasticity in the developing visual cortex, provided that the LTD-LTP crossover point (the modification threshold, theta(m)) varies as a function of the history of cortical activity. Here we provide direct experimental evidence that the value of theta(m) depends on sensory experience. We find in visual cortex of light-deprived rats that LTP is enhanced and LTD diminished over a range of stimulation frequencies, and that these effects can be reversed by as little as two days of light exposure. Our findings support the idea that a variable synaptic modification threshold allows synaptic weights in neural networks to achieve a stable equilibrium.

Animals↗
PubMed1995

Co-regulation of long-term potentiation and experience-dependent synaptic plasticity in visual cortex by age and experience.

Long-term potentiation (LTP) is a lasting enhancement of excitatory synaptic transmission that follows specific patterns of electrical stimulation. Although the mechanism of LTP has been intensively studied, particularly in the hippocampus, its significance for normal brain function remains unproven. It has been proposed that LTP-like mechanisms may contribute to naturally occurring, experience-dependent synaptic modifications in the visual cortex. The formation of normal binocular connections within the visual cortex requires simultaneous input from both eyes during a postnatal critical period that can be delayed by rearing animals in complete darkness. To explore the role of LTP in this experience-dependent maturation process, we induced LTP in visual cortical slices taken at different ages from light-reared and dark-reared rats. Susceptibility to LTP coincides with the critical period and, like the critical period, can be prolonged by rearing animals in darkness. These findings support the hypothesis that LTP reflects a normal mechanism of experience-dependent synaptic modification in the developing mammalian brain.

Aging↗
PubMed1995

Elementary forms of synaptic plasticity in the visual cortex.

The neocortex is an important site of memory storage, and memories are believed to be formed in the cortex by the activity-dependent modification of synaptic connections. However, in contrast to the hippocampus where there has been an increasingly sophisticated analysis of synaptic plasticity, relatively little is known about the mechanisms of synaptic modification in neocortex. Here we summarize the results of a series of experiments conducted on slices of visual cortex in vitro, aimed at elucidating the elementary mechanisms of synaptic plasticity in the superficial layers of neocortex. We show that long-term potentiation (LTP) and depression (LTD) result from high- and low-frequency conditioning stimulation, respectively, of the middle layers of cortex. Both forms of synaptic plasticity are input-specific and dependent on activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors. The critical variable in determining the sign of the synaptic modification appears to be the level of postsynaptic depolarization during conditioning stimulation. The data support a model in which the state of correlation of pre- and post-synaptic activity is converted by the voltage-dependent NMDA receptor channel into a graded postsynaptic Ca2+ signal. LTD is triggered by a modest but sustained elevation in postsynaptic Ca2+, while LTP is elicited by larger changes in Ca2+. An important variable that regulates synaptic plasticity in the neocortex is intracortical inhibition, which constrains the patterns of activity that can reach the modifiable synapses in layer III.

Calcium↗
PubMed1994

1% amino acid peritoneal dialysate: single-cycle study in diabetic patients with end-stage renal disease.

Uremia is associated with multiple abnormalities of carbohydrate and protein metabolism, which are partially corrected by continuous ambulatory peritoneal dialysis with dextrose-based solutions. The hormonal and metabolic effects of amino acid (AA)-based peritoneal dialysis have been studied in nondiabetic uremic patients. Such solutions may be particularly suitable for diabetic patients with end-stage renal disease provided the safety and efficacy of such solutions can be established. We have studied and compared the metabolic and hormonal responses to a single-cycle exchange of dextrose versus a 1% AA-based continuous ambulatory peritoneal dialysis solution in six diabetic patients with end-stage renal disease. In the fasting state and under similar free insulin concentrations, use of the AA solution led to a higher mean glucose concentration (109 +/- 16 mg/dL with dextrose solution v 128 +/- 25 mg/dL with AA solution, P < 0.05). Levels of alanine, lactate, pyruvate, glycerol, non-esterified fatty acids, and triglycerides were similar with the use of either solution. Use of the AA-based solution led to increases in the mean values of the branched chain AAs for the period of the study (valine 131 +/- 10 mumol/L with dextrose solution v 331 +/- 40 mumol/L with AA solution, P < 0.01; leucine 72 +/- 7 mumol/L with dextrose solution v 129 +/- 11 mumol/L with AA solution, P < 0.01; isoleucine 48 +/- 5 mumol/L with dextrose solution v 103 +/- 11 mumol/L with AA solution, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Determinants of single photon response variability.

The responses to single photon absorptions (quantum bumps) vary randomly in size in Limulus photoreceptors. This variability is a natural consequence of simple chemical reactions involving a small number of molecules. The measured size distributions differ significantly from the exponential distribution predicted by the simplest transduction cascade models, one feature of which is that light-activated rhodopsin (R*) is turned off in a single step process. As shown in the companion paper, the nonexponential size distributions can be accounted for if R* is turned off in a multi-step process. This would lead to a nonexponential (peaked) distribution in the number of G-protein molecules activated during a quantum bump and to a nonexponential distribution in the size of bumps. To test this possibility we measured the distribution of quantum bump size under two conditions in which the variability in the number of activated G-proteins was eliminated. eliminated. In one method, bumps were produced by direct activation of single G-proteins using GTP-gamma-S; in the second GDP-beta-S reduced the R* gain to the point where most quantal events were due to activation of a single G-protein. In both cases the size distribution of bumps became much closer to an exponential distribution than that of normal light-induced bumps. These results support the idea that the size distribution of light-induced bumps is dependent on events at the R* level and reflects to the multi-step deactivation of R*.

Animals↗
PubMed1994

Hebbian synapses in visual cortex.

We discovered in slices of rat visual cortex that reliable long-term potentiation (LTP) of synaptic responses in layer III could be elicited by theta burst stimulation delivered to a site in the middle of the cortical thickness, corresponding mainly to layer IV. This synaptic plasticity was reflected in the extracellular field potentials and intracellular EPSPs in layer III, but was not observed in the intracellular responses of layer V neurons, suggesting a preferential involvement of synapses on layer III neurons. Tetanus-induced LTP in this preparation was input specific, and was blocked by application of an NMDA receptor antagonist (but not by an antagonist of nitric oxide synthase). In addition, LTP of layer IV-evoked responses could also be produced reliably by pairing low-frequency synaptic stimulation (approximately 100 pulses at 1 Hz) with strong intracellular depolarization of layer III neurons. Thus, LTP in this circuit satisfies the definition of a "Hebbian" modification. Tetanic stimulation of the white matter, in sharp contrast, consistently failed to elicit LTP in layer III unless a GABAA receptor antagonist was applied to the slice. Analysis indicated that the critical difference between layer IV and white matter stimulation was not the magnitude of the responses to single stimuli delivered to the two sites, but that it might lie in the postsynaptic response during high-frequency stimulation. Consistent with this idea, "associative" LTP could be elicited from white matter when converging but independent inputs from the white matter and layer IV simultaneously received tetanic conditioning stimulation. A hypothetical model is presented to account for the differences between layer IV and white matter stimulation. According to this "plasticity gate hypothesis," inhibitory circuitry in layer IV normally acts as a sort of band-pass filter that constrains the types of activity patterns that can gain access to the modifiable synapses in layer III. By stimulating in layer IV, we have bypassed this filter and therefore do not need to block GABAA receptors to achieve the threshold for LTP in layer III.

Action Potentials↗
PubMed1994

Homosynaptic long-term depression in the visual cortex.

We have investigated the characteristics and mechanism of activity-dependent decreases in synaptic effectiveness in visual cortex. Repetitive, low-frequency stimulation (LFS) of either layer IV or the white matter of visual cortical slices was shown to result in a long-term depression (LTD) of intra- and extracellularly recorded synaptic responses in layer III. In preparations in which responses to stimulation of two independent pathways could be monitored, LFS of one pathway produced LTD of responses to test stimulation of that input only, showing that this form of LTD is homosynaptic. This form of LTD was dependent on the frequency and/or pattern of conditioning stimulation and on activation of NMDA receptors. Okadaic acid, an inhibitor of protein phosphatases 1 and 2a, inhibited LTD, but had no effect on induction of long-term potentiation. In all of these respects, LFS-induced LTD in visual cortex closely resembles what has been recently documented in hippocampus. The combined data support a model in which LTD is triggered by a modest elevation in postsynaptic Ca2+ and activation of protein-serine, threonine phosphatases.

Animals↗
PubMed1993

Common forms of synaptic plasticity in the hippocampus and neocortex in vitro.

Activity-dependent synaptic plasticity in the superficial layers of juvenile cat and adult rat visual neocortex was compared with that in adult rat hippocampal field CA1. Stimulation of neocortical layer IV reliably induced synaptic long-term potentiation (LTP) and long-term depression (LTD) in layer III with precisely the same types of stimulation protocols that were effective in CA1. Neocortical LTP and LTD were specific to the conditioned pathway and, as in the hippocampus, were dependent on activation of N-methyl-D-aspartate receptors. These results provide strong support for the view that common principles may govern experience-dependent synaptic plasticity in CA1 and throughout the superficial layers of the mammalian neocortex.

Action Potentials↗
PubMed1993

Neocortical long-term potentiation.

LTP is a form of activity-dependent synaptic plasticity that has been investigated mainly in the hippocampus. It is considered likely that similar mechanisms may also account for aspects of naturally occurring plasticity in the neocortex. Consequently, an increasing number of studies have been devoted to the investigation of neocortical LTP. Recent results suggest that at least two forms of LTP coexist in layer III of the neocortex. One depends on NMDA-receptor activation and resembles the LTP observed in hippocampal field CA1. A second form is independent of NMDA receptors and requires activation of voltage-sensitive Ca2+ channels.

Animals↗
PubMed1992

Action potentials produce a long-term enhancement of M-current in frog sympathetic ganglion.

M-current is a voltage-gated K+ current that can be turned off by the muscarinic action of acetylcholine. We examined the effects of postsynaptic action potential firing on the level of M-current in B-cells of the bullfrog sympathetic ganglion. High frequency stimulation of action potentials induced an approximately two-fold increase in the level of the M-current that could last up to 35 min. The 'enhanced' M-current was similar to the 'resting' one in its time-dependence, voltage-dependence and sensitivity to neurotransmitters. Experiments were undertaken to examine the functional consequences of the enhanced M-current. Following high frequency stimulation the number of spikes evoked by depolarizing current was reduced. In addition, the excitatory postsynaptic potential (EPSP) evoked by maximal input became subthreshold, thereby blocking information flow through the ganglion cell. These results indicate that the enhancement of M-current by spikes provides a negative feedback mechanism for the control of excitability. It has been reported that postsynaptic stimulation of ganglion cells also produces a long-term increase in the nicotinic EPSP, but we were unable to confirm this observation.

Action Potentials↗
PubMed1992

Mechanisms of amplification, deactivation, and noise reduction in invertebrate photoreceptors.

In this review we have discussed the problem of deactivation at both the rhodopsin and G protein levels. Of particular interest is the novel observation that rhodopsin deactivation can be modulated by light. This modulation is likely to play an important role in light adaptation by reducing the gain of transduction. One interesting possibility is that this modulation involves the phosphorylation of an arrestin-like molecule, but this remains to be tested. One of the experimental advantages of Limulus photoreceptors is the large size of the single photon responses and the fact that even single G proteins produce a detectable response. This made possible the observation that nonhydrolyzable GTP analogues produce discrete transient events rather than the step-like events that would be predicted by previous models. This observation led us to a new view of how enzyme deactivation is coupled to GTP hydrolysis on G protein. According to this view, enzymes are activated by G protein, but can be deactivated by processes that are not dependent on G protein or the hydrolysis of GTP. We have conducted several types of experiments, including some on the vertebrate rod system, that strongly support this hypothesis. A second major theme of this review is transduction noise. The available biochemical evidence suggests that both G protein and G protein-activated enzymes are likely to become spontaneously active and generate undesirable noise. Our measurements indicate, however, that this noise is orders of magnitude smaller than would be predicted by simple models, suggesting that special mechanisms must exist for suppressing this noise. We have proposed a specific mechanism by which enzymes regulated allosterically by multiple subunits could act as coincidence detectors to reduce transduction noise. Finally, there is the fundamental question of which second messengers have a direct role in invertebrate phototransduction. After Fesenko et al. (1985) showed that the light-dependent conductance in vertebrate rods was modulated by cGMP and not by Ca2+, there was rapid progress in understanding the vertebrate photoreceptor transduction mechanism. Now that it has been established that invertebrate light-dependent channels are regulated by cGMP and not by Ca2+, we can expect rapid progress in understanding invertebrate phototransduction. A key question that needs to be answered is whether the InsP3-Ca2+ pathway somehow triggers changes in cGMP or whether there is an altogether different pathway by which cGMP metabolizing enzymes are affected by light.

Adaptation, Physiological↗
PubMed1991

Muscarinic suppression of the M-current is mediated by a rise in internal Ca2+ concentration.

The role of intracellular Ca2+ in the muscarinic suppression of M-current was examined. Intracellular injection of Ca2+ buffer into cells in the intact ganglion reduced the response to muscarinic agonist. In similar experiments on isolated cells, Ca2+ buffer was introduced into the cytoplasm using a perfused recording pipette. Ca2+ buffer (20 mM) with the free Ca2+ concentration set to normal resting levels produced a reversible reduction of the muscarinic response. In a second line of investigation, it was found that pharmacological procedures designed to deplete internal stores of Ca2+ produced a decrease in the muscarinic response. These results, taken together with previous work, support the hypothesis that the muscarinic suppression of M-current is mediated by the release of Ca2+ from intracellular stores.

Animals↗
PubMed1990

The nutritional/metabolic and hormonal effects of 8 weeks of continuous ambulatory peritoneal dialysis with a 1% amino acid solution.

Circulating intermediary metabolites, hormones and plasma amino acids (AA) were measured at intervals over 24 hours in seven non-diabetic patients with chronic renal failure treated by continuous ambulatory peritoneal dialysis (CAPD), before and after an 8-week period during which a 1% amino acid dialysis solution replaced two of the four dextrose exchanges. Mean 24-hour concentrations of plasma total and essential amino acid were higher following the AA dialysate (total pre: 2893 +/- 185; total post: 3357 +/- 244; p less than 0.05; essential pre: 751 +/- 47; essential post: 1064 +/- 57 mumol/l; p less than 0.001). Mean 24-hour concentrations of the branched chain amino acids leucine, isoleucine and valine were higher following the AA dialysate (valine pre: 201 +/- 18; valine post: 321 +/- 19; p less than 0.001; leucine pre: 102 +/- 6; leucine post: 127 +/- 9; p less than 0.01; isoleucine pre: 67 +/- 5; isoleucine post: 85 +/- 7 mumol/l; p less than 0.05). Serum albumin increased with use of the AA dialysate (pre: 36 +/- 1; 2 weeks, 40 +/- 1; 4 weeks, 40 +/- 1; 6 weeks, 41 +/- 1; 8 weeks, 38 +/- 2 g/l). 24-hour profiles and mean 24-hour concentrations of blood glucose, serum insulin, serum triglyceride, plasma non-esterified fatty acids (NEFA), plasma 3-hydroxybutyrate and plasma alanine were unchanged after the AA period. Plasma bicarbonate decreased with use of the amino acid solution (pre: 21 +/- 1; 2 weeks, 18 +/- 1; 4 weeks, 18 +/- 1; 6 weeks, 16 +/- 1; 8 weeks, 16 +/- 1 mmol/l). Use of a 1% amino acid solution over an 8-week period in CAPD patients improves the plasma amino acid profile but results in a metabolic acidosis. The other endocrine and metabolic abnormalities of uremia remain unchanged.

Adult↗