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Biomedical subjects

G Lynch

Publications and source records attributed to G Lynch.

At least 451 records · Page 25Linked to original sources
PubMed1979

Regulation of glutamate receptors by cations.

Current evidence suggests that glutamate is a major excitatory neurotransmitter in the mammalian central nervous system (CNS); particularly, glutamate excites most neurones in the CNS. Until recently this effect was widely used to study glutamate receptors and to distinguish them from those of other excitatory amino acids. The development of ligand binding studies for many neurotransmitters has facilitated the study of receptors at the molecular level and using these methods we recently reported the existence in hippocampal membranes of pharmacologically distinct sodium-dependent and sodium-independent glutamate binding sites, the former related to high-affinity uptake and the latter exhibiting several characteristics of postsynaptic receptor sites. We now report that, as with other neurotransmitters, several ions regulate the Na-independent binding of glutamate; the monovalent cations induce a decreased binding while certain divalent cations enhance this Na-independent binding. Additionally, since some of these effects appear to be irreversible, we propose that the regulation of glutamate binding by cations might account for the extremely long-lasting potentiation of synaptic responses found in the hippocampus following bursts of repetitive electrical stimulation (see ref. 9 for a review).

Animals↗
PubMed1979

The effect of collateral sprouting on the density of innervation of normal target sites: implications for theories on the regulation of the size of developing synaptic domains.

The 'commissural' innervation of the dentate gyrus molecular layer has been analyzed in normal adult rats and in those in which the ipsilateral entorhinal cortex had been removed by aspiration at 14 days post-natal. This ablation severely deafferents the distal two-thirds of the molecular layer and induces 'sprouting' by the commissural afferents which are normally restricted to the more proximal dendritic zone. It was the objective of the present study to employ quantitative electron microscopy to determine (1) the extent of synaptic recovery in the deafferented field; (2) the magnitude of the contribution by the commissural fibers to the reinnervation of the deafferented field; and (3) if sprouting by the commissural projections causes a reduction in the density of the terminal field they generate in their normal target region. The synaptic density of the neonatally deafferented middle molecular layer was found to have returned to near control levels by adulthood. Degeneration studies performed in the adult revealed that commissural endings were located in equivalent numbers in the inner and middle molecular layers of rats in which the entorhinal cortex had been removed at 14 days post-natal; in normal rats (i.e. no neonatal surgery) the commissural terminals were found only in the inner molecular layer. Furthermore, and most importantly, the density of commissural terminals in the inner molecular layer was virtually identical in the 'sprouted' and control rats. Thus the tremendous areal expansion of the commissural terminal field which occurs after early deafferentation of the distal parts of the granule cell dendrites was not accompanied by any loss of input to the normal target of this afferent. Therefore, sprouting in this system represents an exaggeration of normal growth rather than a redistribution of a fixed population of endings. The relevance of these findings to theories concerned with the regulation of axonal growth and terminal proliferation during development is discussed.

Aging↗
PubMed1979

Terminal proliferation in the partially deafferented dentate gyrus: time courses for the appearance and removal of degeneration and the replacement of lost terminals.

The time courses for the appearance and removal of degenerating terminals and the loss and reappearance of intact terminals were investigated in the partially denervated inner molecular layer of the dentate gyrus of the adult rat. Dense degeneration was evident in the neuropil within 26 hours following contralateral hippocampectomy. These profiles increased rapidly in number until the maximal degree was reached at two to three days postlesion, after which the degenerating terminals were quickly removed from the neuropil. A more rapid rate of removal occurred during the 3-to 5-day survival period than from 6 to 50 days postlesion. The intact terminal population dropped 35% within two days of the lesion and remained at this level until six to eight days postlesion when the number began to steadily increase. The time course for this reappearance can be divided into two phases: a period of rapid terminal addition from 6 to 15 days followed by a phase of slower acquisition. This recovery continued until the normal synaptic density was regained by 50 to 65 days postlesion. These results indicate that a substantial proportion of degenerating endings are removed well in advance of the time at which terminal proliferation begins, suggesting that certain changes other than merely the removal of competitive inputs must take place prior to growth of new terminals. Possible explanation suggested by the present results for the delay in the onset of sprouting include: (1) an absence of appropriate postsynaptic targets during the 2-to 5-day postlesion period and (2) inhibition of axonal growth by the glial cells which are phagocytizing the degenerating products. Beyond the sixth postlesion day the rate at which new terminals appear does correlate with the rate at which degeneration is removed. This suggests that once underway the time course for sprouting may be determined by the avaiabliity of postsynaptic sites.

Afferent Pathways↗
PubMed1979

Activity of dentate granule cells during learning: differentiation of perforant path input.

Experiments were conducted which extended previous findings regarding the activity of the perforant path and its synaptic relationship to the granule cells of the dentate gyrus during conditioning. A differential conditioning paradigm was utilized in which rats were trained to respond to one of two different tone frequencies. Results demonstrated that (1) tone elicited averaged evoked potentials recorded from the perforant path terminal zone in the outer molecular layer of the dentate gyrus were similar for both the positive and negative tones regardless of frequency or reversal of the reinforcement condition; (2) extracellular unit discharge patterns of dentate granule cells were differentially associated with the positive and negative tones as demonstrated by post stimulus histograms (PSHs); (3) this differential pattern of unit discharges could be reversed following establishment of criterion differential behavioral responding after reversal of the reinforcement contingency between the two tone stimuli and (4) the differential unit discharge pattern was not present when behavioral responding was not differentiated to the two tone stimuli, e.g., immediately following reversal of the reinforcement contingency. The results are discussed within the context of other anatomically defined functional circuits within the hippocampus which could serve as the basis for alteration of the non differentiated excitatory perforant path input into a differential dentate granule cell discharge pattern for behaviorally relevant sensory stimuli.

Acoustic Stimulation↗
PubMed1979

The relationship between extracellular calcium concentrations and the induction of hippocampal long-term potentiation.

The effect of varying calcium and magnesium concentrations was observed on the development of long-term potentiation (LTP) in the CA1 region of the rat hippocampus maintained in vitro. Treatments which would be expected to lower the depolarization-induced influx of calcium into neuronal elements (i.e. lowering Ca2+ or raising Mg2+ in the perfusion medium) selectively antagonized LTP, while synaptic transmission, paired-pulse and frequency facilitation, as well as short-term (or post-tetanic) potentiation were all maintained. This suggests that LTP is unrelated to these short-term forms of plasticity, but is either a calcium-dependent process itself, or is dependent upon some other calcium-related phenomenon (such as transmitter release).

Animals↗
PubMed1979

Synaptically identified hippocampal slow potentials during behavior.

Averaged evoked slow-wave potentials (AEPs) were recorded from various locations within the dentate gyrus and CA1 field of the hippocampus of 16 rats during the performance of an operant tone discrimination task. Consistent time-locked tone averaged evoked potentials (AEPs) were recorded from the perforant path zone in the outer molecular layer of the dentate gyrus. Tone AEPs were never present in this region (1) prior to development of the discrimination, (2) during behavioral extinction, or (3) during the performance of other operant behaviors. Results are discussed in terms of the functions of the perforant path in neural and behavioral plasticity.

Acoustic Stimulation↗
PubMed1979

Proliferative and migratory activity of glial cells in the partially deafferented hippocampus.

The proliferative response of the glial cell population of the adult rat hippocampus deafferented by unilateral lesion of the entorhinal cortex was studied using 3H-thymidine autoradiography. Two experimental paradigms were used, involving: (1) intraventricular 3H-thymidine injection at a number of post-lesion intervals with sacrifice six hours later and (2) intraventricular injection at 30 hours post-lesion with sacrifice at 6, 96, or 192 hours later. The first increase in the number of labeled glial cells was obtained at 20 hours post-lesion and was confined to areas of degenerating axons. By 30 hours a large and uniformly dense proliferative response was observed throughout the ipsilateral, and medial aspects of the contralateral, hippocampus encompassing both deafferented and intact regions. Cell division continued through 50 and 65 hours post-lesion particularly in directly deafferented regions, but diminished to control levels by 80 hours. Although oligodendroglia and astrocyte-like cells were sometimes found to have incorporated the label the most common proliferative element within the hippocampus corresponded to previous light microscopic descriptions of "microglial" cells. The experiments using thymidine injection given at the peak proliferative period followed by survival periods of varying lengths indicated that a progressive redistribution of labeled nuclei occurred resulting in an accumulation of labeled cells in the zones of deafferentation. Multiple division of cells within these areas as well as the migration of nuclei from non-deafferented regions was found to contribute to this effect. The possible involvement of glial proliferation with other morphological effects of deafferentation, including the sprouting response of intact afferents, is discussed.

Animals↗
PubMed1979

Synaptic phosphoproteins: specific changes after repetitive stimulation of the hippocampal slice.

Repetitive stimulation (100 pulses per second for 1 second) of the Schafer collateral-commissural system of the rat hippocampus induces long-term potentiation of synaptic strength and produces significant changes in the subsequent endogenous phosphorylation of a 40,000-dalton protein from synaptic plasma membranes. This effect is not observed after stimulation in calcium-deficient media or after simulation at the rate of one pulse per second for 100 seconds. These findings provide evidence that repetitive synaptic activation can alter the phosphorylation machinery of the synaptic region and suggest a biochemical process which may be involved in the production of neuronal plasticity.

Animals↗
PubMed1979

A microdrive for use with glass or metal microelectrodes in recording from freely-moving rats.

A new subminiature microdrive assembly is described for electrophysiological recording from behaving rats. This very small, lightweight system allows excellent precision in electrode placement and can maintain stable recordings over extended periods. Since the electrode is nonrotating, tissue damage is minimized. Either metal or glass microelectrodes may be used with the system, offering the possibility of iontophoresis for cell marking or neuropharmacological manipulations.

Animals↗
PubMed1979

A study of protein phosphorylation in shape change and Ca++-dependent serotonin release by blood platelets.

Upon treatment with agents such as thrombin, collagen or concanavalin A, blood platelets change shape, secrete serotonin and phosphorylate two proteins having molecular weights of approximately 20,000 and 40,000. We have analyzed the relationship of this protein phosphorylation to shape change and release aided by the fact that while shape change occurs independently of extracellular calcium, release of serotonin displays a rather strict calcium requirement. Under limited calcium conditions, where virtually no serotonin release occurs, (Con A)-stimulated phosphorylation is uninhibited. Divalent cations (Mg++, Co++ and Zn++) also inhibit release but not phosphorylation. The microtubule effectors colchicine and D2O show concomitant effects on release and phosphorylation, indicating a microtubule involvement prior to phosphorylation. Papaverine inhibits release and phosphorylation while not strongly influencing shape change, suggesting that shape change does not require phosphorylation. We therefore conclude that phosphorylation of these proteins takes place after shape change but prior to release, and although it may be required for secretion to occur, the two processes are easily separated. Thus phosphorylation of these proteins is not likely to be an integral component of the release mechanism.

Animals↗