Much has been learned over the past 15 years about the mechanisms of synaptic plasticity and their relationships to learning and memory processes. Some of the questions raised 15 years ago have been answered while others still remain elusive. This brief review attempts to evaluate the progress accomplished in this field and discusses four specific issues: (i) the relationships between mechanisms of synaptic plasticity and memory types, (ii) the relationships between stabilization of synaptic modifications and memory consolidation, (iii) the links between gene regulation and regulation of synaptic efficacy, and (iv) the relationships between synaptic dynamics and synaptic plasticity. Although it is relatively easy to identify areas in which progress has been made, it is also clear that many areas remain highly controversial and will keep neuroscientists busy for years to come.

Animals↗

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Effects of two ACTH analogs on successive odor discrimination learning in rats.

Olfactory discrimination learning has been shown to provide a powerful tool to investigate the mechanisms involved in the formation, storage and retrieval of information in rodent CNS. In the present study we tested the effects of two ACTH analogs, which were previously reported to influence the processes of learning and memory, on various olfactory learning tasks. The ACTH(4-9) analog HOE 427 produced an apparent increase in storage of olfactory information as shown by the difficulty experienced by the animals to rapidly reverse their behavioral responses to previously learned odors. Similarly, the ACTH (4-9) analog ORG 2766 appears to enhance the storage of olfactory information when administered either before or after the learning trials. These data are consistent with the notion that ACTH and related analogs facilitate performance in a variety of learning tasks. In addition, our results suggest possible mechanisms by which some neuroactive peptides might modulate learning and memory processes in the CNS.

Adrenocorticotropic Hormone↗

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Low levels of calpain activity in Chiroptera brain: implications for mechanisms of aging.

Calcium-dependent neutral proteases ("calpains") have been implicated in degenerative processes in muscles and neurons, suggesting that they might also play a role in age-related brain pathologies and perhaps in brain aging itself. Because Chiroptera exhibit an unusual maximum life span, relative to other mammalian orders, we investigated the activity of these enzymes in the brain of two species of bats. As in other mammals, brain calpain degrades many proteins associated with the cell cytoskeleton. However, enzyme activity is 5-7 fold lower in bat's brain than in a similar-sized mammal, such as the mouse. Moreover, the maximal life span of bats predicted from the equation relating calpain activity and maximal life span across a wide range of mammals is close to the observed values. These results strengthen the hypothesis that calpain activity is somehow linked to the rate at which brains age.

Aging↗

PubMedDate not supplied

Calcium dependent aspects of synaptic plasticity, excitatory amino acid neurotransmission, brain aging and schizophrenia: a unifying hypothesis.

(1) The functional and structural reorganization of dendritic spines by calcium activated proteases is postulated to play a causal role in the production of the phenomenology of brain aging and in particular in the development of pathology and degeneration. Excitatory neurotransmission appears to be essential for the development of irreversible synaptic changes. (2) One of the genes modified in schizophrenia is postulated to be directly or indirectly linked to the control of excitatory neurotransmission; possibly the normal switching on of the expression of the adult form of the NMDA receptor is altered, resulting in an inappropriate functioning of this receptor. This genetic characteristic might explain the apparent resistance of schizophrenic brains to aging.

Aging↗

PubMedDate not supplied

Effect of thyroidectomy on oxidative phosphorylation mechanisms in rat liver mitochondria.

(1) In the presence of succinate, 2,4-dinitrophenol raised the oxygen consumption rate of state 3 liver mitochondria, whatever the thyroid state. The rise was clearly greater in thyroidectomized than in normal rats, but the uncoupled state 3 mitochondria of thyroidectomized rats nevertheless consumed oxygen more slowly than normal rat mitochondria. Thyroidectomy therefore weakened respiratory chain activity and phosphorylation reactions. (2) With beta-hydroxybutyrate as substrate, oxygen consumption V of state 3 mitochondria was greatly diminished in thyroidectomized rats, but the KM remained unchanged. In the presence of succinate, state 3 respiration was not affected by thyroidectomy when substrate concentrations were low, but diminished at concentrations above 3 mM. (3) Respiratory chain activity was estimated by determining the succinate cytochrome c reductase activity. After thyroidectomy, catalytic efficiency (V/KM) dropped by 60% in intact mitochondria at high concentrations of the substrate, but only by 30% when concentrations were low. In submitochondrial particles, thyroidectomy reduced V without changing KM. These results suggest that in thyroidectomized rats, succinate penetration is faster when substrate concentrations are low. (4) Mg2+ -stimulated ATPase activity dropped by 20% in thyroidectomized rats. In the presence of increasing concentrations of oligomycin, inhibition of ATPase activity was greater in normal than in thyroidectomized rat mitochondria. Thyroidectomy reduced by over 30% the ATPase activity actually involved in oxidative phosphorylation.

2,4-Dinitrophenol↗

PubMedDate not supplied

Regulation of glutamate receptor binding by the cytoskeletal protein fodrin.

The erythrocyte cytoskeleton, which consists primarily of a meshwork of spectrin and actin, controls cell shape and the disposition of proteins within the membrane. Proteins similar to spectrin have recently been found in diverse cells and tissues, and it is possible that they mediate the capping of cell-surface receptors, although this has not been demonstrated directly. In neurones, the spectrin-like protein fodrin lines the cortical cytoplasm and may link actin filaments to the membrane. Fodrin has been hypothesized to regulate the number of receptor binding sites on neuronal membranes for the putative neurotransmitter L-glutamate. Micromolar calcium concentrations activate the thiol protease calpain I, induce fodrin degradation and more than double the density of glutamate binding sites; these effects are all blocked by thiol protease inhibitors. We have now used specific antibodies to examine further the role of fodrin proteolysis in regulating glutamate receptors. We report that fodrin antibodies block the fodrin degradation and increase in glutamate binding normally induced by calcium, and so provide direct evidence for control of membrane receptors by a non-erythroid spectrin.

Animals↗

PubMedDate not supplied

Excitatory amino acids inhibit stimulation of phosphatidylinositol metabolism by aminergic agonists in hippocampus.

Since the initial observations in the 1950s a large number of neurotransmitters and hormones have been shown to influence phosphatidylinositol (PI) metabolism in brain and peripheral ganglia (see ref. 3 for review). This has led to the suggestion that PI is part of an intracellular second messenger system for some types of diffusible chemical factors. Consistent with this are recent reports that one of the products of PI turnover (diacylglycerol) stimulates the Ca-dependent phospholipid-dependent protein kinase (kinase C) while a second (inositol trisphosphate) causes the release of calcium from intracellular stores. Thus it is possible that at least some brain neurotransmitters utilize the PI system to produce functional effects that are in addition to and which outlast the very brief physiological responses they elicit. Although it had been anticipated that another class of receptors might inhibit receptor-mediated stimulation of PI breakdown, no clear examples of such effects have been described. We now report that acidic amino acids, which are that acidic amino acids, which are thought to be excitatory neurotransmitters at the majority of brain synapses, strongly inhibit the stimulation of PI metabolism elicited by carbachol, histamine, or by potassium-induced depolarization, without changing the response to noradrenaline. As well as indicating a novel function for the excitatory amino acids, these results suggest that the central nervous system possesses cell-cell interactions of a previously unsuspected type.

Amino Acids↗