Motor and associative deficits in D2 dopamine receptor knockout mice

Abstract

Behavioral abnormalities produced by D2 dopamine receptor gene deletion in mice have been attributed either to resulting Parkinson-like features (i.e. response slowing and response initiation difficulties) or to behavioral deficits contributed by alleles of the originating 129Sv strain. Three strategies were used to address these conflicting hypotheses: (1) we used mice congenic at n10 backcross into the C57BL/6 line to minimize the 129Sv contribution; (2) we compared mice that were wild-type (+/+), heterozygous (+/-), or homozygous (-/-) for the D2 gene with the two most relevant inbred lines (129Sv and C57BL/6) and (3) we used both conventional and novel behavioral assessment methods. Behavioral attributes were expressed in terms of locomotor activity, wall rearing, rotarod performance, operant response acquisition, operant response performance, lick dynamics (force, rhythm), grip strength, and tremor in response to harmaline challenge. Results showed that, compared to controls, the -/- mice exhibited longer duration wall rears, retarded operant response acquisition, increased latencies to move from the operandum to the reward well, and exaggerated response to harmaline. Age was investigated as a variable (10-11 weeks versus 41-44 weeks of age) in the locomotor activity and wall rear assessments. A gene dosage effect (deficits in the +/- mice) on these two variables became apparent in the older mice. Taken together, the results showed that mice without the D2 gene exhibited Parkinson-like behavioral features that were not easily attributed to alleles contributed by the 129Sv strain, but were consistent with basal ganglia dysfunction.

Motor coordination deficits in mice lacking RGS9

“…In particular, RGS9 KO mice display deficits in motor coordination and working memory, but show normal responses in other tasks. Deficits in motor coordination and working memory are consistent with abnormal regulation of dopamine signaling in the striatum or prefrontal cortex, respectively (Fowler et al, 2002;Glickstein et al, 2002;Kellendonk et al, 2006). This is the first demonstration of the role of RGS9 in endogenously mediated complex behavior, as opposed to effects of exogenously applied drugs of abuse.…”

“…Indeed, RGS9-2 over-expression diminishes sensitivity to the behavioral effects of dopamine agonists, while loss of RGS9 has the opposite effect . Alterations in dopamine signaling are known to result in deficits in motor coordination (Fernagut et al, 2003;Fowler et al, 2002;Kelly et al, 1998). While we feel that the motor coordination deficit seen in the RGS9 KO mice likely reflects a deficit in fine motor control, other possible explanations for the rotarod deficit are valid.…”

Locomotor activity is regulated by D2‐like receptors in Drosophila: An anatomic and functional analysis

“…wiley.com. ] weeks of age, while the homozygous (À/À) mutants display significant motor deficits at 10 weeks of age (Fowler et al, 2002;Fetsko et al, 2005).…”

“…These receptors have been classified based on (i) the presence of distinctive amino acid sequence motifs, (ii) sensitivity to subtype specific agonist and antagonist ligands, and (iii) signal transduction coupled to either stimulatory Gs (D1-like receptors), or inhibitory Gi/o, (D2-like receptors) G proteins. The development of primate and rodent models with altered dopamine receptor mediated signaling utilizing either pharmacologic (i.e., with receptor subtype specific ligands) or genetic (i.e., by targeted gene disruption) interventions has provided critical insights about the physiologic processes mediated by these receptors (Baik et al, 1995;Fowler et al, 2002). Consequently, it was established that the mammalian D2R subtype is a key modulator of locomotor function.…”

Motor deficits and altered striatal gene expression in aphakia (ak) mice

“…Rotarod-The rotarod apparatus (Accurotor, Accuscan Instruments, Columbus, OH, USA) provides a sensitive means to measure deficits of motor coordination resulting from defects of the dopaminergic system (Baquet et al, 2004;Fetsko et al, 2005;Fowler et al, 2002;Iancu et al, 2005). Each mouse (n= ak -60, wt -54) was given three trials over 3 days on an accelerating protocol (0-40 rpm in 80 seconds).…”