Behavioral alterations in mice deficient for the extracellular matrix glycoprotein tenascin-R

doi:10.1016/S0166-4328(03)00109-8

Behavioural Brain Research

Volume 145, Issues 1–2, 17 October 2003, Pages 189-207

https://doi.org/10.1016/S0166-4328(03)00109-8 Get rights and content

Abstract

We investigated the behavior of mice deficient for the extracellular matrix (ECM) glycoprotein tenascin-R (TN-R) in comparison to their wild-type (WT) littermates. A longitudinal study including tests for exploration and anxiety, motor coordination and cognition was carried out. Mice were tested at different ages, ranging from 3 weeks to 11 months and under different housing conditions. TN-R deficient mice displayed decreased motivation to explore and an increased anxiety profile in the free choice open field (FCOF), open field (OF) and elevated plus maze (EPM) tests. Moreover, the anxiety level of TN-R deficient mice was more strongly influenced by environmental factors as compared to WT littermates. TN-R deficient mice showed motor coordination impairments in the wire hanging, Rotarod and pole test. Thus TN-R ablation leads to an altered behavioral phenotype in mice that may negatively affect their fitness under natural conditions.

Introduction

The extracellular matrix (ECM) of the brain is a specialized composition of macromolecules that serves not only as a scaffold for the cohesion of nervous tissue, but plays an important role in cell differentiation, cell migration, neurite outgrowth and cell communication. Tenascin-R (TN-R) is a member of the tenascin family of glycoproteins and a major component of the ECM in the central nervous system (CNS). Apart from a possible expression by Schwann cells during embryogenesis [25], TN-R is restricted to the CNS, where it is expressed by oligodendrocytes particularly during myelination and by neuronal cells, such as horizontal cells, motor neurons, stellate and basket cells [3], [37]. TN-R is found on unmyelinated and myelinated axons, on oligodendrocytes and on the outer aspects of myelin sheaths and is particularly accumulated at the nodes of Ranvier [3], [13] and in perineuronal nets (PN), a specialized form of ECM [8], [9], [38]. Due to its dual function in vitro, where it has been shown to be either repulsive or adhesive, TN-R was formerly named janusin in the style of the two-headed god (for review see Ref. [31]). TN-R has been found to play an important role in synaptic plasticity of the hippocampus via modulation of perisomatic inhibition and of long-term potentiation (LTP) [29].

To elucidate the glycoproteins function in vivo, a null mutant was generated [35]. TN-R deficient mice are viable and fertile and TN-R expressing brain areas are apparently normal. A very prominent feature of TN-R deficient mice is an altered morphology of PN [6], [18], [35]. At nodes of Ranvier localization of the chondroitin sulfate proteoglycan phosphacan, a binding partner of TN-R [39], is strongly decreased and mice show a reduced conduction velocity in the optic nerve [35]. Electrophysiological recordings revealed that TN-R deficient mice display a disturbed balance between excitation and inhibition in the hippocampus and show a twofold decrease in theta-burst stimulation induced LTP in the CA1 region of the hippocampus [7], [30], correlating with ultrastructural abnormalities in synapses [24].

TN-R is a phylogenetically conserved protein [11], [12] suggesting that it is important for the expression of an adaptive phenotype. Adaptive behavior is of paramount importance for the survival and fitness of an individual, since it represents the response of an organism towards different internal (physiological) and external (environmental) demands and situations. Therefore, behavioral analyses are essential for evaluating how a determined perturbation could affect the fitness of an individual. Since behavior is the end-point of integrated systems, even subtle alterations in any of the components are likely to be reflected in a disrupted or modified behavior. We performed a longitudinal study on TN-R deficient mice, analyzing and interpreting behavior from an ethological perspective that takes into consideration the social and environmental conditions in which animals are tested as well as the adaptive function of the behavior analyzed.

Section snippets

Husbandry

Mice were transferred from the breeding facility into a vivarium with an inverted 12-h light:12-h dark cycle (light on at 07:00 h) and maintained under standard housing conditions (21±1 °C, 40–50% humidity, food and water ad libitum). All behavioral tests were performed during the dark cycle of the animals in a room next to the vivarium that was illuminated with dim red light. Tests were started and ended at least 2 h after light offset and 2 h before light onset, respectively. The experimental

General appearance

No obvious difference in the appearance of TN-R deficient mice (KO) in comparison to their wild-type (WT) littermates was observed when mice were examined starting from PD 21. No difference was found in body weight as regularly recorded from weaning up to 4 months of age (Fig. 1). At the age of 11 months, KO mice were slightly but significantly heavier than WT mice (WT: 34.6±1.3 g; KO: 38.6±1.1 g, P<0.05).

Aggressive interactions with HET littermates

The observation of aggressive interactions performed until mice were isolated at the age of

Discussion

Weber et al. [35] generated a mouse deficient for the ECM glycoprotein TN-R to investigate the molecule’s functions in vivo. Since then, TN-R deficient mice have been studied extensively under morphological and electrophysiological aspects and considerable abnormalities were found [6], [7], [18], [24], [30], [35]. However, the behavioral phenotype of this mutant has not yet been described. We therefore performed tests for different behavioral parameters, including motor coordination,

Acknowledgements

The authors are grateful to Achim Dahlmann for genotyping, Ali Derin for animal care and Deutsche Forschungsgemeinschaft (SCHA 185) for support.

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Research reportBehavioral alterations in mice deficient for the extracellular matrix glycoprotein tenascin-R

Abstract

Introduction

Section snippets

Husbandry

General appearance

Aggressive interactions with HET littermates

Discussion

Acknowledgements

Behav. Brain Res.

Physiol. Behav.

Behav. Brain Res.

Neuroscience

Brain Res. Brain Res. Rev.

Trends Neurosci.

Behav. Brain Res.

Curr. Opin. Cell Biol.

Trends Neurosci.

Brain Res.

Neurosci. Biobehav. Rev.

Pharmacol. Ther.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Neurosci. Biobehav. Rev.

Mol. Cell. Neurosci.

Neurosci. Lett.

J. Biol. Chem.

J. Biol. Chem.

Expression of janusin (J1-160/180) in the retina and optic nerve of the developing and adult mouse

Glia

Research report
Behavioral alterations in mice deficient for the extracellular matrix glycoprotein tenascin-R