Purkinje Cell Expression of a Mutant Allele ofSCA1in Transgenic Mice Leads to Disparate Effects on Motor Behaviors, Followed by a Progressive Cerebellar Dysfunction and Histological Alterations

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract. Work presented here describes the behavioral and neuropathological course seen in mutant SCA1 transgenic mice. Behavioral tests indicate that at 5 weeks of age mutant mice have an impaired performance on the rotating rod in the absence of deficits in balance and coordination. In contrast, these mutant SCA1 mice have an increased initial exploratory behavior. Thus, expression of the mutant SCA1 allele within cerebellar Purkinje cells has divergent effects on the motor behavior of juvenile animals: a compromise of rotating rod performance and a simultaneous enhancement of initial exploratory activity. With age, these animals develop incoordination with concomitant progressive Purkinje neuron dendritic and somatic atrophy but relatively little cell loss. Therefore, the eventual development of ataxia caused by the expression of a mutant SCA1 allele is not the result of cell death per se, but the result of cellular dysfunction and morphological alterations that occur before neuronal demise.

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…This study was performed on naïve animals only. Mice were placed on the rotarod apparatus (Ugo Basile) for four trials per day for 4 consecutive days (Clark et al, 1997). Each trial lasted a maximum of 10 min, divided into an initial part in which the rotarod underwent a linear acceleration from 4-40 rpm over the first 5 min of the trial and then remained at maximum speed for the remaining 5 min.…”

“…After coating the hind feet of the mice with a non-toxic paint, animals were allowed to walk through a dark, 40-cm long, 9-cm wide, 6-cm high tunnel, and the footprint patterns made on the paper lining the floor of the tunnel were scored for four step parameters (Clark et al, 1997).…”

“…We analyzed DTg and control mice. Mice were placed into the center of a 70 6 100 cm open arena containing a 10 6 10 cm gridded floor, for 15 min per test for six consecutive days (Clark et al, 1997). On the fourth day of testing, an enriched open-field test was performed by placing three different objects in the arena.…”

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

“…2,3 This mouse, known as the B05 model, develops progressive disease, with many features similar to SCA1 including measurable gait deficits by 7 weeks of age. Additionally, there are transcriptional changes by postnatal day 25 and PC loss by 24 weeks of age.…”

“…Additionally, there are transcriptional changes by postnatal day 25 and PC loss by 24 weeks of age. 3 Earlier, a doxycycline-inducible form of the B05 model revealed that pre-existing phenotypes were reversible after many weeks of mutant ATXN1 expression. 4 This suggests that a window of opportunity exists not only for halting the disease, but perhaps also to reverse the presence or severity of symptoms once present.…”