Abstract The learning and memory deficits associated with non‐pathological ageing mainly result from alterations to the plasticity of neuronal network dynamics within the hippocampus. In addition to the broad spectrum of changes that affect the morphology and function of hippocampal excitatory circuits in the ageing brain, the impaired activation of the N ‐methyl‐ d ‐aspartate subtype of glutamate receptors ( NMDA ‐R) is a typical feature, altering the induction and maintenance of long‐term potentiation, a major form of synaptic plasticity. In addition to glutamate, the binding of a co‐agonist at the strychnine‐insensitive glycine‐binding site is required for NMDA ‐ R activation. This review presents recent evidence that: (i) the amino acid d ‐serine is an endogenous co‐agonist of synaptic NMDA ‐R and necessary for long‐term potentiation expression, (ii) reduced d ‐serine levels in the hippocampus contribute to synaptic plasticity and memory deficits in normal ageing, and (iii) age‐related oxidative stress selectively targets hippocampal serine racemase to impact d ‐serine availability in neuronal networks. These results emphasize the critical role of the hippocampal d ‐serine‐dependent pathway in changes affecting neuronal network dynamics in physiological ageing that underlie memory deficits. In addition, the central role of serine racemase in these changes opens new perspectives in the search for relevant therapeutic strategies aimed at reducing age‐related memory defects.
The possible role of endogenous cholinergic innervation in hippocampal plasticity is controversial. We studied the role of acetylcholine (ACh) in short- and long-term potentiation (STP and LTP), using the cholinergic neurotoxin 192 IgG-saporin. It was still possible to induce STP the LTP in the CA1 field following complete and selective cholinergic denervation of the hippocampus. This study therefore demonstrates that integrity of the endogenous cholinergic system is not necessary for the induction or maintenance of LTP in the CA1 field of the hippocampus. The consequences in terms of relationship between hippocampal cholinergic system, LTP and memory are discussed.
Abstract The activity of the olivocerebellar complex and the structures related in series with it have been studied using the complementary action of harmaline and 3‐acetylpyridine to isolate the two principal inputs to the cerebellar Purkinje cells. The activities of the various nuclei as well as the entire brain have been simultaneously monitored using the [ 14 C]2‐deoxyglucose method under the various combined effects of the pharmacological agents. (1) Tremogenic doses of harmaline increased the frequency of discharge in selected parts of the olivocerebellar system, increasing climbing fiber input and reducing Purkinje cell simple spike discharges in corresponding parts of the cerebellar cortex. The metabolic activity increased in the inferior olive and in the red nucleus. The results are interpreted as a net reduction of Purkinje cell inhibition on their target neurons, leading to a facilitatory cerebellar output. (2) Systemic injection of neurotoxic doses of 3‐acetylpyridine selectively produced total degeneration of the neurons in the inferior olive, resulting in the suppression of complex spikes and a net increase in simple spike output from the Purkinje cells. The metabolic consequences were a reduction or absence in the inferior olive, decrease in the red nucleus, and increases in the Purkinje cell target neuron regions, including the intracerebellar and vestibular nuclei. The study of long survival times following the neu‐ rotoxic treatment revealed a transient metabolic marking of the inferior olive during the active glial processes accompanying the degeneration. In other parts the radioautographic changes caused by the destruction of the inferior olive persisted for about 1 month after the administration of the drug. (3) Tremogenic doses of harmaline were given to rats at different times following treatment with 3‐acetylpyridine. It was demonstrated that: (a)intoxication of the inferior olive started within the second hour after 3‐acetylpyridine administration, corresponding to the time at which the metabolic response to harmaline was also abolished; and (b) the increased metabolic activity produced by harmaline in the olivocerebellar complex was a consequence of an increased activity of the neurons of the inferior olive rather than a direct pharmacological effect of the drug. (4) Partial lesions of the inferior olive led to increased metabolic activity of those parts of the intracerebellar nuclei topographically related to the destroyed parts of the inferior olive. (5) In 3‐acetylpyridine‐treated animals, local ablation as well as local inactivation of the cerebellar cortex produced localized suppression of the intense labeling in the intracerebellar nuclei obtained in these animals. Since these regions receive synapses which are normally inhibitory, suppression of labeling clearly supports the hypothesis that regional marking may very well be produced by the activity of the presynaptic terminals themselves. The increased marking following suppression of the olivocerebellar system was thus interpreted as due to an increased activity in the simple spikes, producing an increased inhibitory influence of the Purkinje cell and therefore a disfacilitatory cerebellar output.
THE consequences of intracerebroventricular injection of the toxin 192-lgG-saporin on the electrophysiological properties of CA1 pyramidal cells were investigated using intracellular recordings in the in vitro hippocampal slice preparation. We present the first electrophysiological evidence of a dysfunction of hippocampal cholinergic afferents following injection of 192-lgG-saporin. The synaptic events mediated by acetylcholine were altered in such animals: the slow cholinergic excitatory postsynaptic potentials as well as the cholinergic activation of GABAergic interneurones were dramatically depressed or even absent; the amplitude and duration of the afterhyperpolarization following a burst of spikes were increased, while other neuronal properties were not modified. These specific alterations suggest that the toxin 192-lgG-saporin is a specific tool for the experimental study of cholinergic denervation in the hippocampus.
Summary Age‐associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N ‐methyl‐D‐aspartate receptor (NMDAr)‐dependent long‐term potentiation (LTP) in CA1 hippocampal slices indicates that the glial‐derived neuromodulator d ‐serine is required for the induction of synaptic plasticity. During aging, the content of d ‐serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr‐mediated synaptic potentials in old rats are rescued by exogenous d ‐serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of d ‐serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.
Introduction D ‐serine in the brain: regional expression and synaptic turnover D ‐serine regulation of synaptic transmission and plasticity D ‐serine signalling in normal aging and Alzheimer's disease D ‐serine signalling and schizophrenia Conclusions Abstract Rather different from their initial image as passive supportive cells of the CNS, the astrocytes are now considered as active partners at synapses, able to release a set of gliotransmitter‐like substances to modulate synaptic communication within neuronal networks. Whereas glutamate and ATP were first regarded as main determinants of gliotransmission, growing evidence indicates now that the amino acid D ‐serine is another important player in the neuronal‐glial dialogue. Through the regulation of glutamatergic neurotransmission through both N ‐methyl‐ D ‐aspartate (NMDA‐R) and non‐NMDA‐R, D ‐serine is helping in modelling the appropriate connections in the developing brain and influencing the functional plasticity within neuronal networks throughout lifespan. The understanding of D ‐serine signalling, which has increased linearly in the last few years, gives new insights into the critical role of impaired neuronal‐glial communication in the diseased brain, and offers new opportunities for developing relevant strategies to treat cognitive deficits associated to brain disorders.
1. gamma-Aminobutyric acid (GABA)-mediated inhibitory postsynaptic potentials (IPSPs) were compared in young and aged rats in CA1 area of the rat hippocampus, with the use of the in vitro intracellular recording technique. D-2-Amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were used to suppress synaptic potentials mediated by the excitatory amino acids. 2. Under these conditions, stimulation of the stratum radiatum elicited a monosynaptic fast GABAA (fIPSP) and a slow GABAB (sIPSP)-mediated IPSP. The fIPSP and the sIPSP were further isolated in the presence of the GABAB antagonist CGP 35348 or the GABAA antagonists bicuculline or picrotoxin. No age-related changes were observed in the amplitude and the duration of the fIPSP. In contrast, the amplitude (but not the duration) of the sIPSP was significantly reduced in the aged rat. 3. The postsynaptic hyperpolarization and increase in membrane conductance induced in pyramidal cells by bath application of the GABAB agonist baclofen were comparable in both groups of animals, indicating that the postsynaptic GABAB receptors are not altered in the aged rats. 4. Paired-pulse depression of IPSPs was used in young and aged rats to study possible alterations in GABA release or in presynaptic GABAB receptors that control GABA release. When fIPSPs were isolated by bath application of tetrahydro-9-aminoacridine (THA), no significant difference in the magnitude of the paired-pulse depression was observed between young and aged rats. A similar result was found with the paired-pulse depression of isolated sIPSPs in the presence of bicuculline or picrotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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