Meis1 effects on motor phenotypes and the sensorimotor system in mice

Abstract

MEIS1 encodes a developmental transcription factor and has been linked to restless legs syndrome (RLS) in genome-wide association studies. RLS is a movement disorder leading to severe sleep reduction and has a substantial impact on the quality of life of patients. In genome-wide association studies, MEIS1 has consistently been the gene with the highest effect size and functional studies suggest a disease-relevant downregulation. Therefore, haploinsufficiency of Meis1 could be the system with the most potential for modeling RLS in animals. We used heterozygous Meis1-knockout mice to study the effects of Meis1 haploinsufficiency on mouse behavioral and neurological phenotypes, and to relate the findings to human RLS. We exposed the Meis1-deficient mice to assays of motor, sensorimotor and cognitive ability, and assessed the effect of a dopaminergic receptor 2/3 agonist commonly used in the treatment of RLS. The mutant mice showed a pattern of circadian hyperactivity, which is compatible with human RLS. Moreover, we discovered a replicable prepulse inhibition (PPI) deficit in the Meis1-deficient animals. In addition, these mice were hyposensitive to the PPI-reducing effect of the dopaminergic receptor agonist, highlighting a role of Meis1 in the dopaminergic system. Other reported phenotypes include enhanced social recognition at an older age that was not related to alterations in adult olfactory bulb neurogenesis previously shown to be implicated in this behavior. In conclusion, the Meis1-deficient mice fulfill some of the hallmarks of an RLS animal model, and revealed the role of Meis1 in sensorimotor gating and in the dopaminergic systems modulating it.

Differential Dopamine D1 and D3 Receptor Modulation and Expression in the Spinal Cord of Two Mouse Models of Restless Legs Syndrome

“…Further, the lack of function of the inhibitory D3 receptor in the isolated spinal cord in vitro was sufficient to increase the number or large-reflex spinal reflex amplitudes when compared to WT controls (Clemens and Hochman, 2004 ). Similar to D3KO, Meis1KO show a pattern of hyperactivity but contrary to D3KO, express no significant nociceptive differences in a hotplate test (Salminen et al, 2017 ). This is consistent with our findings under baseline conditions where Meis1KO and WT express similar withdrawal thermal pain latencies, whereas reflex latencies are decreased in D3KO (Figure 1 ).…”

“…Mouse models for a dysfunctional D3 receptor (D3KO) and Meis1 (Meis1KO) were developed independently (Accili et al, 1996 ), and each animal expresses some features associated with RLS in the clinic. Both D3KO and Meis1KO express increased locomotor activity (Accili et al, 1996 ; Salminen et al, 2017 ), but only D3KO show an increased sensory excitability both in the isolated spinal cord (Clemens and Hochman, 2004 ) and in vivo (Keeler et al, 2012 ). The thermal pain withdrawal reflex depends on spinal cord circuits that can be recruited experimentally to assess compromised function of the underlying neural networks, both with the spinal cord and extending into the periphery.…”

PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes

“…It is notable that studies of a mouse models of another RLS oligogene, Btbd9 , also identified effects on sleep . Mice with altered expression of Btbd9 , the RLS oligogene Meis1 , and Ptprd each exhibited increased locomotion (termed restlessness in one report), but none manifest clear‐cut periodic limb movements.…”

A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons

“…The Social Discrimination procedure involved using ovariectomised 129Sv stimulus females as shown previously 19,21 . Measures included time spent in social investigation ("social affinity") and a social recognition index ("social memory").…”