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S A Mackler

Publications and source records attributed to S A Mackler.

32 records · Page 2Linked to original sources
PubMed1992

Stimulus-induced coordinate changes in mRNA abundance in single postsynaptic hippocampal CA1 neurons.

The molecular effects of use-dependent changes in synaptic transmission were studied in individual CA1 pyramidal neurons from rat hippocampal slices. Potentiation of excitatory postsynaptic currents was associated with coordinate changes in the relative abundance of several mRNAs 30 min to 3 hr after stimulation. There was a 300% increase in calcium/calmodulin-dependent protein kinase II mRNA levels concordant with a 50% decrease in protein kinase C beta 1 isoform mRNA. A 2-fold increase in zif-268 mRNA was seen, while increases in c-fos and c-jun mRNA levels were inconsistent, gamma-Aminobutyric acid A receptor beta 1 subunit mRNA levels increased 3-fold. Potentiation-induced changes were prevented by N-methyl-D-aspartate receptor blockade. Changes in mRNA abundance in individual cells, with synaptic and glial interactions intact, combine to produce a molecular fingerprint of a potentiated CA1 neuron.

Animals↗
PubMed1992

Cocaine abuse.

Explore the source record for details and available documents.

Cocaine↗
PubMed1991

The molecular biology of addictive drugs.

The additive drugs alcohol, morphine, cocaine, and amphetamine are each associated with the development of tolerance and physical dependence. Changes in gene expression occur in cell culture and in vivo with the administration of these centrally-acting drugs. This article reviews those experiments that have studied drug-induced alterations in gene transcription. Ethanol has diverse effects on the amounts of messenger RNA molecules within the central nervous system. Ion channels, neuropeptides, membrane receptors, and immediate early genes represent several regulated mRNAs. The effects are selective, however, as many other specific products are not altered. Evidence for a genetic predisposition to ethanol use reinforces the importance of the genotype. Opioids, cocaine, and amphetamine also affect gene transcription. Messenger RNAs studied have included many of those demonstrated to be altered by alcohol use. Interestingly, use of any of these drugs alters the expression of immediate early genes. These genes may represent an initial step in the pathway that leads to drug addiction. The composite of drug-induced changes in gene expression results in the cellular responses of tolerance and dependence. The characterization of these changes should provide a better understanding of the molecular mechanisms of drug addiction.

Alcoholism↗
PubMed1987

The axon reaction of lamprey spinal interneurons.

Axotomy and partial denervation of giant interneurons (GIs) and lateral cells (LCs) were produced by complete spinal transection in the larval lamprey spinal cord. Both cell types demonstrated a reduction in cytoplasmic basophilia, increase in cell size, nuclear eccentricity, and formation of a chromophilic nuclear cap. This was quantified in the case of cell diameter. During the first 8 weeks of recovery, the GIs with the largest diameters were found progressively further from the scar and this peak change moved at approximately 0.5 mm/day. The increase in size of GIs remained up to 20 weeks post-transection, long after the time required for their axons to regenerate across the scar and form functioning synapses. GIs injected intracellularly with horseradish peroxidase (HRP) also showed this increase in diameter as well as a simplification of their dendritic trees. Intracellular recordings from GIs revealed changes in the frequency and amplitude of spontaneous synaptic input. In the first two weeks after transection, spontaneous excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) were less frequent than in control cells. After 6 weeks of recovery they became more frequent than in control cells. EPSPs predominated in axotomized GIs, while in control cells they constituted only 36% of the total of spontaneous potentials. A reversible increase in the amplitude of these EPSPs occurred at 3-4 weeks of recovery time. The resting membrane potential was significantly reduced by the 6th week after transection and returned to normal after the 22nd week.

Animals↗
PubMed1987

Specificity of synaptic regeneration in the spinal cord of the larval sea lamprey.

1. Pairs of central neurones in large larval sea lampreys were impaled with micro-electrodes and studied for synaptic connexions in both unoperated control animals and animals which had recovered from complete spinal transection. Two identified classes of neurones served as post-synaptic targets: giant interneurones (g.i.s) and lateral cells (l.c.s). Several identified neurone types were tested as potential sources of presynaptic input. 2. When synaptic potentials had short, fixed latencies they also persisted during activation of the presynaptic cell at 3.3-33.3 Hz and were not eliminated after addition of lamprey saline containing high (20 mM) Ca2+. These presumably represented monosynaptic connexions. Variable-latency responses were eliminated by faster rates of stimulation of the presynaptic cell and were mediated via polysynaptic pathways. 3. In control animals, g.i.s received monosynaptic input from more caudal g.i.s in fourteen of thirty-two tested cell pairs. These excitatory post-synaptic potentials (e.p.s.p.s) were composite electrochemical responses. The amplitudes of the earlier electrical component averaged 1.66 +/- 0.24 mV (mean +/- S.E. of mean) and the amplitude of the later chemical component averaged 0.79 +/- 0.05 mV. 4. In operated larvae, eight of forty-seven g.i.-g.i. pairs separated by the transection scar were connected by monosynaptic composite e.p.s.p.s. In these pairs the electrical component averaged 0.84 +/- 0.17 mV (P less than 0.05 vs. control) and the chemical component averaged 1.56 +/- 0.40 mV. The average conduction velocity between these cells was less than that in control g.i.-g.i. pairs (0.93 +/- 0.11 vs. 1.61 +/- 0.25 m/s; P less than 0.01). 5. The l.c.s showed monosynaptic e.p.s.p.s after activation of a subset of the bulbar Müller neurones (B2-4) in seven of twelve pairs. In behaviourally recovered larvae three of twenty-two similar pairs separated by the transection scar were also connected via monosynaptic e.p.s.p.s. The average conduction velocity between these experimental neurones was also less than that in control bulbar-l.c. pairs (1.03 +/- 0.03 vs. 1.58 +/- 0.09 m/s; P less than 0.001). 6. Several types of neurones were either infrequently linked or never connected to g.i.s or to l.c.s in control larvae. In animals which had recovered from a spinal transection, no synaptic connexions were found from such neurones on to g.i.s or l.c.s respectively, in 124 tested cell pairs. In addition, dorsal cells (intraspinal primary sensory neurones) received no synaptic input upon stimulation of the spinal cord before or after transection.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Functional regeneration following spinal transection demonstrated in the isolated spinal cord of the larval sea lamprey.

Axons in the larval sea lamprey can regenerate across the site of a spinal cord transection and form functioning synapses with some of their normal target neurons. The animals recover normal-appearing locomotion, but whether the regenerating axons and their synaptic connections are capable of playing a functional role during this behavior is unknown. To test this, "fictive" swimming was induced in the isolated spinal cord by the addition of D-glutamate to the bathing solution. Ventral root discharges of segments above and below a healed transection showed a high degree of phase-locking. This strongly suggests that the behavioral recovery is mediated by regenerated functional synaptic connections subserving intersegmental coordination of the central pattern generator for locomotion.

Action Potentials↗
PubMed1986

Determinants of directional specificity in the regeneration of lamprey spinal axons.

The projection patterns of regenerating spinal axons in the larval sea lamprey (Petromyzon marinus) were determined by intracellular injection of HRP. Four hundred and eighty-six of 562 stained axons and axon-like neurites (87%) arising from Muller and Mauthner axons, giant interneurons, and dorsal cells terminated in an orientation similar to that of their counterpart control cells. Therefore, lamprey spinal axons regenerate selectively along their normal projection paths. During the first 4 weeks of recovery, i.e., before any had regenerated beyond the transection site, 91 of 114 axons and long neurites (80%) projected in the proper direction. Thus, the correctness of the final projection patterns did not result from selective retraction of randomly directed long neurites. When the cords were doubly transected 1 cm apart, orientation of regenerating neurites remained normal both within the 1 cm island and in the adjacent spinal cord. This suggests that the directional specificity of axonal regeneration was determined neither by the location of the scar nor by the availability of channels formed by the degenerating fibers. Finally, removing 1 cm of spinal cord eliminated potential synaptic targets for regenerating axons on either side of the lesion, but did not affect the direction of axonal growth. These findings are consistent with the hypothesis that the regeneration of lamprey spinal axons is guided by local chemical cues that persist long after the pathways are formed early in development.

Animals↗
PubMed1985

Regeneration of functional synapses between individual recognizable neurons in the lamprey spinal cord.

In 4- to 5-year-old sea lamprey larvae that had recovered from complete transection of the spinal cord, pairs of giant interneurons on opposite sides of the scar were impaled with microelectrodes. In 4 of 30 pairs, stimulation of the caudal cell elicited a monosynaptic electrochemical excitatory postsynaptic potential in the rostral cell. Fifty percent of such pairs were synaptically linked in control lampreys without transections. These results show regeneration of functional synaptic connections between individual neurons in a vertebrate central nervous system.

Animals↗
PubMed1984

Directional specificity in the regeneration of lamprey spinal axons.

After spinal transection in ammocoetes (lamprey larvae) 4 to 5 years old, functional recovery is accompanied by a limited regeneration in which axons grow as far as 5 millimeters beyond the scar. In axotomized giant interneurons labeled intracellularly with horseradish peroxidase 16 to 120 days after transection, 74 percent of regenerating neurites grew in their normal projection pattern, rostal and contralateral to the cell body. One third of the neurites originated anomalously from posterior dendrites. Despite their initial abnormal orientation, 80 percent of these neurites looped contralaterally and rostrally to assume the normal projection path. The directional specificity persisted when giant interneurons were located in islands formed by double simultaneous cord transection. This limited regeneration seems to be characterized by directional selectivity that cannot be attributed to nonspecific influences, such as a tendency of neurites to grow in an already established direction or a trophic effect of the zone of injury.

Animals↗
PubMedDate not supplied

Cocaine selectively alters neurotransmitter receptor mRNAs in mouse embryos.

Alterations in gene expression due to in utero cocaine exposure may adversely affect nervous system development. The present study examined whether or not cocaine administration to pregnant mice alters embryonic mRNA levels for several developmentally-regulated genes. Antisense RNA amplification was performed using RNA from LM/Bc embryos at gestational days 9.5 and 10.5 after three days of cocaine treatment. This technique highlights simultaneous changes that occur in the expression of many genes after a teratogenic insult. Significant changes occurred in the expression pattern on only four genes from a total of 42 candidate cDNAs. These included increases in the relative levels of the alpha and beta 1 subunits of the GABAA receptor without concurrent changes in the non-NMDA glutamate receptor subunits. The results support the hypothesis that in utero cocaine exposure leads to specific changes in gene expression that may ultimately contribute to developmental abnormalities.

Animals↗