Elsevier

Behavioural Brain Research

Volume 172, Issue 1, 15 September 2006, Pages 24-32
Behavioural Brain Research

Research report
Neurological abnormalities in caveolin-1 knock out mice

https://doi.org/10.1016/j.bbr.2006.04.024Get rights and content

Abstract

Caveolin-1 is the defining structural protein in caveolar vesicles, which regulate signal transduction and cholesterol trafficking in cells. In the brain, cav-1 is highly expressed in neurons and glia, but its function in those cell types is unclear. Mice deficient in cav-1 (CavKO) have been developed to test functional roles for cav-1 in various tissues. However, neurological phenotypes associated with loss of cav-1 in mice have not been evaluated. Here, we report the results of motor and behavioral testing of CavKO mice. We find that mice deficient in cav-1 have reduced brain weight and display a number of motor and behavioral abnormalities. CavKO mice develop neurological phenotypes including clasping, abnormal spinning, muscle weakness, reduced activity, and gait abnormalities. These data suggest that cav-1 is involved in maintaining cortico-striato-pallido-thalamo-pontine pathways associated with motor control.

Introduction

Caveolin proteins are the major component of vesicles called caveolae, which regulate membranous trafficking, signal transduction, and cholesterol efflux [1], [2]. To date, three members of the caveolin family (cav-1, -2, and -3) have been identified, all of which are expressed in a tissue-specific manner. Relatively little is known about caveolae and the regulation of caveolin expression. However, their roles in some cellular functions are emerging. For example, it has been well documented that expression of cav-1 is important in the lung and the heart [3], [4], [5], [6]. Loss of cav-1 in mice results in cardiac hypertrophy [5], pulmonary defects including thickening of alveolar septa caused by endothelial cell proliferation and fibrosis [3]. Cav-1 knock out (CavKO) mice are leaner and display a remarkable resistance to high-fat diets [7]. These phenotypes are thought to arise from defects in adipocytes physiology, since loss of cav-1 causes reduced diameter of lipid droplets. Because of its role in lipid transport, cav-1 is being considered as a major factor in hyperlipidemias and obesity.

More recently, cav-1, -2, and -3 have been detected in the brain [8]. Cav-1 and -2 are constitutively and widely expressed in brain microvessels [8], endothelial cells [8], astrocytes [8], [9], [10], oligodenrocytes [10], Schwann cells [11], dorsal root ganglion [12], and hippocampal neurons [13]. Cav-3 is predominantly expressed in astroglial cells [8]. It is not yet clear what unique functions are associated with the three family members. However, localization of cav-1 to growth cones and dendrites of hippocampal neurons [13] have raised the possibility that cav-1 could play an important role in neuronal differentiation and maturation. Cav-1 is detected in a complex with SNAP25 in hippocampal slices in vivo in response to persistent synaptic potentiation [14]. These observations have suggested that the cav-1/SNAP complex may regulate neurotransmission [14]. In support of this hypothesis, cav-1 has been identified as a component of synaptic ribbons, the fusion sites of transmitter vesicles in photoreceptors [15]. The cholesterol binding properties of cav-1 [16], [17], [18], [19], [20] have also suggested a role in membrane remodeling and synaptic plasticity [21], [22]. How cav-1 might regulate neurotransmission or remodel membranes is not known.

In general, specific roles of cav-1 in neurons remain poorly understood. The recent development of knock out animals has provided a useful new tool to probe for functions. However, neurological phenotypes in CavKO animals have not been evaluated. To fill this gap, we have implemented a number of tests designed to detect neuronal abnormalities in mice. We find that neurons in CavKO mice do not degenerate. However, these animals develop neurological phenotypes that implicate a cav-1-dependent role in pathways associated with motor control.

Section snippets

Experimental animals

All protocols were approved by the Institutional Animal Care and Use Committee in accordance with Mayo Clinic institutional animal care guidelines. The following mouse models were used: cav-1 null mice (CavKO) [3], the parental control strain C57BL/6J (Bl6), and homozygous knock-in HD mouse model with 150 CAG repeats (HD) [29]. Mice were housed with a normal light–dark cycle (lights on at 6:00 am, lights off at 8:00 pm) in a clean facility, and given free access to food and water. Both male and

Lifespan, growth and fertility are normal in CavKO mice relative to control animals

We first evaluated the expression of cav-1 in Bl6 mice and CavKO animals. Cav-1 expression in Bl6 was abundant and readily detectable in extracts from whole brain (Fig. 1A and B), striatum (caudate/putamen, C/P), cerebellum (Crb), and hippocampus (Hip) (Fig. 1B). In each region, cav-1 was present as a single 22 kD protein, similar to that expressed in control endothelial cells (Fig. 1A and B, En). As expected, cav-1 was absent in tissues of CavKO animals at any age tested (Fig. 1A). Loss of

Discussion

Here, we report that loss of cav-1 induces distinctive neurological phenotype in mice that progresses with age. Loss of cav-1 results in both structural and functional abnormalities. Notably, loss of cav-1 causes a measurable reduction in brain size and behavioral alterations associated with cortico-striatal, cerebellar and hippocampal regions. These abnormalities do not arise from neuronal loss since it was not detected up to 70 weeks in any brain region tested. In our hands, the neurological

Acknowledgements

This work was supported by the Mayo Foundation (CTM), Hereditary Disease Foundation (CTM), and National Institutes of Health grants NS40738 (CTM), R01 GM 066359 (CTM). We thank Mr. K. Johnson for help with mouse breeding, and Mr. T. Farnham for help with manuscript preparation.

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