Mice deficient in microtubule-associated protein MAP1B show a distinct behavioral phenotype and altered retina function

Abstract

We investigated mice deficient for the microtubule-associated protein MAP1B, a cytoskeletal element highly expressed in the developing nervous system, for altered performance in behavior, learning, and memory. Using the multiple T-maze, the open field and the Morris water maze we found that mice homozygous for a deletion of the MAP1B gene demonstrate impaired locomotor activity most likely correlated to a lack of physical endurance in general. In contrast, there were no significant differences in cognitive function and memory retention. In addition, we performed electroretinography and observed a reduction of the a-wave amplitude in response to single flash, white light stimulation. Taken together, these data provide further evidence for an important role of MAP1B in synaptic neurotransmission.

Introduction

The extraordinary morphology of neurons and glial cells suggested early on that the cytoskeleton of these cells must play a paramount role in their differentiation and function. As a consequence, the discovery of cytoskeletal elements such as microtubule-associated proteins (MAPs) that are expressed specifically in the brain triggered great interest in the function of these proteins. The idea was that expression of these proteins in neurons or glial cells enabled these cells to adapt an otherwise generic cytoskeleton to the special requirements of nerve cells.

Indeed, in the past two decades evidence has been accumulating for the importance of MAPs in brain development and neuronal function. For example, mutations in tau, a low molecular mass MAP, are the cause for a class of human frontotemporal dementias linked to chromosome 17 [21], [40]. Likewise, the high molecular mass protein MAP1B has been implicated in mental retardation and defects in synaptic function observed in the fragile X syndrome in mouse and drosophila model systems [5], [48].

MAP1B belongs to a family of large, fibrous MAPs and is expressed predominantly in the developing nervous system [38], in areas of the adult brain that retain a high degree of plasticity [30], [37], [44], and in the developing and adult peripheral nervous system [8], [12], [23], [35]. Expression can be detected in neurons as well as oligodendrocytes [13], [45] and Schwann cells [23], [35].

Involvement of MAP1B in development of the murine nervous system has been demonstrated in MAP1B mutant mice [11], [16], [26], [41]. The most striking developmental phenotype in MAP1B deficient mice is the lack of the corpus callosum probably due to defects in axon guidance [26]. In addition, MAP1B deficient mice display a 30% reduction of nerve conductance velocity in the sciatic nerve.

In accordance with the original contention, MAP1B has been shown to regulate the dynamics and the stability of microtubules in neurons and in vitro [15], [29], [33]. In addition, MAP1B can bind to actin filaments [29], [34], [43] and is therefore a prime candidate to orchestrate the delicate interplay between microtubules and actin in growth cone migration and guidance. This hypothesis is supported by the finding that local ablation of MAP1B in growth cones impairs growth cone steering [24]. The binding of MAP1B to microtubules and to actin is regulated by phosphorylation [17] and thus subject to extracellular axon guidance cues that alter intracellular protein kinase signal transduction pathways.

However, the regulation of the neuronal cytoskeleton in response to extracellular signals might not be the only role of MAP1B in neurons. It has been shown that MAP1B is expressed in neurons and cone photoreceptors [26], [32] and interacts with specific subunits of retinal GABA_C receptors, modulating the affinity of these receptors for their ligands [3], [19]. This suggests that MAP1B might be involved in the modulation of the synaptic response in certain neurons of the retina and perhaps other areas of the nervous system.

Given the widespread expression of MAP1B in the nervous system and the gross anatomical and functional defects in MAP1B deficient mice one would expect alterations in behavior and diminished performance in tests probing learning and memory. Initial experiments indicated a decrease in exploring behavior of MAP1B deficient mice. The current study was undertaken to investigate the performance of MAP1B deficient mice in a broad range of behavioral and neurophysiological tests.