A role for synaptic plasticity in the cognitive deficits of Costello syndrome mice

Thijs van der Vaart 1,2,3, Iris Overwater 1,3, Melika Mozaffari 1,3, Mehrnoush Aghadavoud 1,3, Jaga Schreiber 1,3, Ype Elgersma 1,3
1 Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands , 2 Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands3 ENCORE Expertise Center for Neurodevelopmental disorders

Costello syndrome is a rare RASopathy caused by activating mutations in the HRAS gene. Cognitive impairments and behavioral problems are common amongst children with Costello syndrome. To understand the underlying mechanisms of these deficits, mouse models have been developed in which the endogenous HRAS gene has been mutated to express constitutively active HrasG12V, similar to patients. HrasG12V-mice showed spatial learning deficits in the Morris Water Maze, in the absence of motor performance problems or gross brain pathology. We found a marked increase in activity dependent MAPK-phosphorylation in hippocampal tissue. Since Ras-MAPK signaling has been implicated in synaptic plasticity, we subjected HrasG12V brains to hippocampal field recordings. Input/output properties of HrasG12V brains were normal, suggestive of normal anatomy and connectivity. However, synaptic plasticity as measured by the ability to undergo long-term potentiation (LTP) was affected. These differences were also present in mice that specifically expressed the HrasG12V allele in neurons. Taken together, our data suggests a role for impaired synaptic functioning in the mechanisms of cognitive deficits of Costello syndrome. Ras-inhibitors are currently being tested to see whether the cognitive phenotype of HrasG12V mice is reversible.