Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior

Abstract

Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

“…The strong RSK2 expression in the habenula suggests that the kinase contributes to a number of habenula-mediated behavioral responses. Further, habenular lesions in the rat produced effects comparable to the deficits observed in mrsk2 KO mice (Thornton and Evans, 1984;Lecourtier and Kelly, 2007;Poirier et al, 2007;Darcq et al, 2011). Our finding that local RSK2 knockdown in the habenula reduces morphine analgesia, together with data from habenular lesions, highlight the important role of RSK2 in regulating morphine responses in the habenula.…”

“…The latter includes impairments of spatial working memory, delayed acquisition of spatial reference memory and long-term spatial memory. In addition, disinhibition and difficulties adapting to a new environment, observed in mutant mice, likely contribute to the cognitive deficits (Poirier et al, 2007). Our study examines major responses to opiates, including analgesia, indicates that prior lithium exposure does not influence morphine analgesia.…”

“…mrsk2 KO mice recapitulate some of the human symptoms, including peripheral deficits in glycogen metabolism of skeletal muscle (Dufresne et al, 2001) and lipodystrophy (ElHaschimi et al, 2003), as well as central effects on cognition (Poirier et al, 2007). The latter includes impairments of spatial working memory, delayed acquisition of spatial reference memory and long-term spatial memory.…”

The p90 RSK Family Members: Common Functions and Isoform Specificity

“…Although the observed mutations in RSK2 are heterogeneous, they all result in loss of kinase activity (7). Moreover, knockout of Rsk2 in the mouse leads to a phenocopy of the human disease (8), and our own unpublished findings suggest that morpholino-mediated downregulation of RSK2 in the developing zebrafish embryo also reproduces some aspects of the human disease. These aspects include spinal deformity, reminiscent of the scoliosis observed in humans, often combined with tail shortening as well as cardiac hypertrophy.…”

Coffin–Lowry syndrome

“…Behavioral studies revealed normal motor coordination, but a profound retardation in spatial learning and a deficit in long-term spatial memory, providing evidence that RSK2 has similar roles in mental functioning in both mice and humans. 30 The cortical dopamine level was found increased in mrsk2_KO mice and was accompanied with an over-expression of dopamine receptor type 2 and the dopamine transporter. 31 Data strongly supported the notion that the dopaminergic dysregulation may be caused by a tyrosine hydroxylase hyperactivity.…”