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Stress, cognitive impairment and cell adhesion molecules

Key Points

  • There is increasing evidence that stress is a potent modulator of brain and cognitive function. Brief activation of physiological stress systems during learning can facilitate memory consolidation, but chronic exposure to stress could have deleterious effects on brain structure and function, which might be manifested immediately or as a long-term vulnerability to cognitive deficits.

  • This review focuses on recent findings that highlight a role for neuronal cell adhesion molecules (CAMs) of the immunoglobulin superfamily — that have important roles in synaptic function and circuit remodelling — as probable mediators of chronic stress-induced cognitive and neural alterations.

  • Stress affects the brain at various levels, from neuronal structure and synaptic plasticity, to cognition and behaviour. The CA3 hippocampal subregion seems to be particularly sensitive to the detrimental effects of sustained stress, but alterations in dendritic arborization have also been found in other areas, including CA1, the amygdala and the prefrontal cortex.

  • A series of studies have shown that chronic stress can markedly affect hippocampal CAM expression. A chronic restraint procedure was found to diminish neural cell adhesion molecule (NCAM) but increase expression of another neuronal CAM, L1, in the hippocampus.

  • Glucocorticoids probably participate in stress-induced regulation of CAMs through a concerted action with other factors. Excitatory amino acids and neurotrophic factors have also been implicated in this process.

  • Experimental protocols that alter CAM expression or impair CAM function can mimic some of the effects of chronic stress. For example, inhibiting NCAM expression results in structural changes in the CA3 region, as seen in chronically stressed rats.

  • NCAM-derived or -mimicking peptides are currently being developed for their potential efficacy in modulating NCAM function, with the aim of treating neural and cognitive disorders. One of these peptides was found to enhance presynaptic function, promote synapse formation and induce a long-lasting improvement of hippocampus-dependent memories.

Abstract

Stress has profound effects on brain structure and function, but the underlying mechanisms are still poorly understood. Recent studies imply that neuronal cell adhesion molecules of the immunoglobulin superfamily — NCAM and L1 — are important mediators of the effects of stress on the brain. Chronic stress regimes that lead to hippocampal atrophy and spatial-learning impairment in rodents simultaneously induce a pattern of changes in cell adhesion molecule expression that fits with a role for these molecules in stress-induced neuronal damage and neuroprotective mechanisms. These findings highlight cell adhesion molecules as potential therapeutic targets to treat stress-related cognitive disturbances.

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Figure 1: Structural features of CA3 pyramidal cells in chronically stressed animals and NCAM-knockout mice.
Figure 2: Functional implications of stress-induced changes in cell adhesion molecule expression.
Figure 3: Mechanisms by which glucocorticoid receptors can participate in stress-induced reduction of NCAM-140.

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Acknowledgements

Work in the author's laboratory that relates to this topic was supported by grants from the European Union Fifth Framework Program, the Spanish Ministry of Science and Technology, Community of Madrid and by the Swiss Federal Institute for Technology. The author would like to thank previous and current co-workers, C. Venero, M. I. Cordero, K. Touyarot, K. Cambon, J. J. Merino, T. Pinelo, N. D. Kruyt and A. I. Herrero, for their original contributions.

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DATABASES

Entrez Gene

BDNF

CREB

ERK1

ERK2

GR

L1

MR

NCAM

ST8SIAII

ST8SIAIV

FURTHER INFORMATION

Laboratory of Behavioral Genetics

DataSet GSE787

Glossary

AMYGDALA

A small, almond-shaped structure, comprising 13 nuclei, buried in the anterior medial section of each temporal lobe.

PREFRONTAL CORTEX

The non-motor sectors of the frontal lobe that receive input from the dorsomedial thalamic nucleus and subserve working memory, complex attentional processes and executive functions such as planning, behavioural inhibition, logical reasoning, action monitoring and social cognition.

MOSSY FIBRES

Axons of hippocampal granule cells, which form synapses with CA3 pyramidal neurons. Mossy fibre terminals are among the largest in the CNS.

THORNY EXCRESCENCES

Complex dendritic spines located mainly on the proximal apical dendrite and soma of CA3 pyramidal cells, which serve as the postsynaptic target for the mossy-fibre synaptic inputs.

LONG-TERM POTENTIATION

(LTP) An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. LTP is most often studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

MORRIS WATER MAZE

A learning task in which an animal is placed in a pool filled with opaque water and has to learn to escape to a hidden platform that is placed at a constant position. The animal must learn to use distal cues, and the spatial relationship between them and the platform. Learning in this task involves the hippocampus.

SYNAPTOSOMES

A preparation of the presynaptic terminal, isolated after subcellular fractionation. This structure retains the anatomical integrity of the terminal and can take up, store and release neurotransmitters.

LONG-TERM DEPRESSION

(LTD). An enduring weakening of synaptic strength that is thought to interact with long term potentiation (LTP) in the cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.

HOMOPHILIC BINDING

Adhesion that is mediated through attraction between identical molecules expressed by different cells.

SERIAL ANALYSIS OF GENE EXPRESSION

(SAGE) A method for the analysis of gene expression that converts polyadenylated mRNA into cDNA by reverse transcription. Oligonucleotide 'tags' are then hybridized to the cDNA, ligated to form concatemers that are amplified by PCR, and finally cloned and sequenced. The number of tags present indicates the prevalence of the gene, therefore providing a quantitative profile of cellular gene expression.

NEUROBLASTOMA CELLS

An immortalized cell line derived from tumours that arise from the neural crest.

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Sandi, C. Stress, cognitive impairment and cell adhesion molecules. Nat Rev Neurosci 5, 917–930 (2004). https://doi.org/10.1038/nrn1555

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