The serine/threonine protein kinase, ‘Ca2+-calmodulin (CaM)-dependent protein kinase 4’ (CaMK4) regulates gene expression and protein activity in response to Ca2+-stimuli in brain neurons and modulates neuronal function and development, late long-term potentiation, memory formation and cognition [1,2]. Four patients have been identified with a de-novo mutation c.928A>G in the CaMK4 gene (S. McLean, unpublished data), resulting in a M310V variant in the autoinhibitory domain of CaMK4. Clinically, these patients display developmental delays and intellectual disabilities, in some cases accompanied by altered motor function and hypotonia. In studies to investigate if the M310V mutation causes altered CaMK4 function in vitro and in vivo, we performed CaMK4 activity assays in COS-7 cells revealing the M310V mutation results in elevated basal CaMK4 activity. We then generated an equivalent mouse (CaMK4M306V) that was characterized using a range of behavioural assays (n=12 group). Male CaMK4M306V mice displayed altered spatial memory function in the Barnes maze and novel object recognition task, and a trend towards decreased front-paw strength, but no alteration in locomotor activity, or anxiety- and depressive-like behaviours. Together these data support the idea that the clinical symptoms in human carriers of the M310V mutation are caused by the gain-of-function mutation in the CaMK4 gene. Current studies are investigating gene-dosage effects and the impact of the mutation on downstream targets in the CaMK4 signalling pathway in frontal cortex and hippocampus.1. Kang H. et al. (2001) Cell 106, 771–783.2. Ho N. et al. (2000) J Neurosci 20, 6459–6472.