Biomedical subjects

P J Mackenzie

Publications and source records attributed to P J Mackenzie.

6 recordsLinked to original sources

PubMed2003

Co-occurrence of multiple sclerosis and myasthenia gravis in British Columbia.

We describe eight patients with associated multiple sclerosis (MS) and myasthenia gravis (MG). Patients were less than 50 years old at the time of onset, and seven were female. The clinical course of both MS and MG was mild in most patients. To our knowledge, this represents the largest reported series. We provide further evidence for a nonrandom association of these two diseases and discuss common mechanisms of pathogenesis.

Adult↗

PubMed2000

Vesicle number does not predict postsynaptic measures of miniature synaptic activity frequency in cultured cortical neurons.

We tested the hypothesis that heterogeneity in the frequency of miniature synaptic activity reflects differences in the number of vesicles present in presynaptic terminals. Using imaging techniques, we measured dendritic miniature synaptic calcium transients attributed to the spontaneous release of single transmitter quanta. Following imaging, the identified neurons were processed for serial transmission electron microscopy. At sites of quantal Ca(2+) transients mediated by N-methyl-D-aspartate receptors, we confirmed the presence of excitatory synapses and measured the total number of vesicles and the number of docked vesicles. We observed no correlation between the frequency of spontaneous miniature activity and either the total vesicle number or the number of docked vesicles. We conclude that the presynaptic vesicle complement as measured by ultrastructural analysis does not necessarily determine the frequency of spontaneous activity at synapses mediated by N-methyl-D-aspartate receptors.

Animals↗

PubMed1999

Ultrastructural correlates of quantal synaptic function at single CNS synapses.

We have tested the hypothesis that functional differences between synapses are associated with ultrastructure in cultured cortical neurons. Using Ca(2+) imaging, we measured NMDA receptor-mediated miniature synaptic calcium transients attributed to the spontaneous release of single transmitter quanta. After imaging, the identified neurons were processed for serial transmission electron microscopy. At sites of quantal NMDA receptor-dependent Ca(2+) transients, we confirmed the presence of excitatory synapses and measured spine size and synaptic contact area. Our results demonstrate that synapse size correlates positively with the amplitude of the NMDA receptor-mediated postsynaptic response, suggesting that larger synapses express a greater number of NMDA receptors. Therefore, regulation of quantal amplitude may involve processes that alter synapse size.

Animals↗

PubMed1998

High safety factor for action potential conduction along axons but not dendrites of cultured hippocampal and cortical neurons.

By using a combination of Ca2+ imaging and current-clamp recording, we previously reported that action potential (AP) conduction is reliably observed from the soma to axonal terminals in cultured cortical neurons. To extend these studies, we evaluated Ca2+ influx evoked by Na+ APs as a marker of AP conduction under conditions that are expected to lower the conduction safety factor to explore mechanisms of axonal and dendritic excitability. As expected, reducing the extracellular Na+ concentration from 150 to approximately 60 mM decreased the amplitude of APs recorded in the soma but surprisingly did not influence axonal conduction, as monitored by measuring Ca2+ transients. Furthermore, reliable axonal conduction was observed in dilute (20 nM) tetrodotoxin (TTX), despite a similar reduction in AP amplitude. In contrast, the Ca2+ transient measured along dendrites was markedly reduced in low Na+, although still mediated by TTX-sensitive Na+ channels. Dendritic action-potential evoked Ca2+ transients were also markedly reduced in 20 nM TTX. These data provide further evidence that strongly excitable axons are functionally compartmentalized from weakly excitable dendrites. We conclude that modulation of Na+ currents or membrane potential by neurotransmitters or repetitive firing is more likely to influence neuronal firing before AP generation than the propagation of signals to axonal terminals. In contrast, the relatively low safety factor for back-propagating APs in dendrites would suggest a stronger effect of Na+ current modulation.

Action Potentials↗

PubMed1996

Ca2+ imaging of CNS axons in culture indicates reliable coupling between single action potentials and distal functional release sites.

A combination of Ca2+ imaging and current clamp recording in cultured cortical neurons was used to evaluate the reliability of coupling between the action potential and rises in Ca2+ at distal release sites as a possible source of variability in CNS synaptic transmission. Local domains of enhanced Ca2+ influx were observed at varicosities on axon collaterals. Functional assay of vesicle turnover using FM1-43 and parallel electron microscopy confirmed that these varicosities were release sites. Single action potentials reliably ( > 95% of the time) resulted in a presynaptic Ca2+ transient at all presumed release sites including those on distal collaterals. Variability in the amplitude of presynaptic Ca2+ transients at individual boutons was estimated to be on average less than 20%. We conclude that the coupling of somatic action potentials to distal release sites is generally a reliable process, although nonlinearity in the relationship between Ca2+ influx and neurotransmitter release may amplify the effects of relatively small fluctuations in Ca2+ influx.

Action Potentials↗

PubMed1992

Muscimol injections into the nucleus basalis magnocellularis of rats: selective impairment of working memory in the double Y-maze.

Anatomical and neurochemical results suggest that the cortico- and amygdalopetal cholinergic neurons of the nucleus basalis magnocellularis (NBM) may receive GABAergic inputs. The present experiments were undertaken to evaluate the possible influence of intra-NBM injections of the GABAA agonist, muscimol, on memory. In two experiments, rats were chronically implanted with guide cannulae placed bilaterally into the NBM. Rats were trained to a criterion of at least 83% correct on each component in a double Y-maze task that allowed a dissociation of working and reference memory. The task began with placement into one of the two end arms of the first Y-maze and the reference memory task was to go to the stem for food. Access to the second Y was then given and the working memory task was to go to the goal arm opposite the arm in the first maze from which that trial began. In experiment 1, pre-trained rats (n = 7) received muscimol (0.5 microliter) in doses of 0, 0.01, 0.1 and 1.0 microgram in a counterbalanced order with re-training to criterion between injections. In experiment 2, pre-trained rats (n = 8) received saline, muscimol (0.1 microgram), the GABAA antagonist, bicuculline (0.01 microgram), and muscimol + bicuculline. Results of experiment 1 revealed that intra-NBM muscimol produced a dose-dependent and differential impairment of working and reference memory. A dose of 0.1 microgram impaired working memory without significantly affecting reference memory; doses of 0.01 microgram and 1.0 microgram affected neither and both types of memory, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗