The kinase function of MSK1 regulates BDNF signaling to CREB and basal synaptic transmission, but is not required for hippocampal long-term potentiation or spatial memory

Abstract

The later stages of long-term potentiation in vitro and spatial memory in vivo are believed to depend upon gene transcription. Accordingly, considerable attempts have been made to identify both the mechanisms by which transcription is regulated and indeed the gene products themselves. Previous studies have shown that deletion of one regulator of transcription, the mitogen- and stress-activated kinase 1 (MSK1), causes an impairment of spatial memory. Given the ability of MSK1 to regulate gene expression via the phosphorylation of CREB at serine 133, MSK1 is a plausible candidate as a prime regulator of transcription underpinning synaptic plasticity and learning and memory. Indeed, prior work has revealed the necessity for MSK1 in homeostatic and experience-dependent synaptic plasticity. However, using a knock-in kinase-dead mouse mutant of MSK1 the current study demonstrates that, whilst the kinase function of MSK1 is important in regulating the phosphorylation of CREB at serine 133 and basal synaptic transmission in hippocampal area CA1, it is not required for mGluR-dependent long-term depression, two forms of long-term potentiation or several forms of spatial learning in the water maze. These data indicate that other functions of MSK1, such as a structural role for the whole enzyme, may explain previous observations of a role for MSK1 in learning and memory.

Significance Statement The nuclear kinase MSK1 has been identified as a possible link between cell-surface neurotransmitter receptors and the gene expression necessary for long-term memory: by coupling the activation of BDNF receptors to the regulation of transcription via the phosphorylation of CREB, MSK1 unites a neurotrophin heavily implicated in synaptic plasticity with changes in gene expression. Using a kinase-dead MSK1 mouse mutant we show that, whilst MSK1 is necessary for CREB phosphorylation and the regulation of basal synaptic transmission, it is not required for mGluR-dependent long-term depression, long-term potentiation or several forms of spatial reference memory. MSK1 may instead play a homeostatic role in the CNS that allows synapses to adapt to prevailing synaptic or sensory experience.