For the last several years we have been determining whether the signaling cascades that normally are required for LTP, LTD, and memory are altered in mouse models of several developmental disorders. In this regard, our laboratory is currently conducting a wide variety of studies on signal transduction, synaptic plasticity, cognitive behaviors, and social behaviors in several mouse models, including models of fragile X mental retardation, Down syndrome, Angelman syndrome, and tuberous sclerosis complex. In addition, recent studies indicate that altered translation control might underlie certain autism spectrum disorders. We have been developing new mouse models with altered translation control and have found that they exhibit several autistic behavioral endophenotypes.
Video of enhanced repetitive behavior in mice with an overexpression of eIF4E.
For examples of our work on this topic, please see:Hoeffer, C.A., Sanchez, E., Hagerman, R.J., Mu, Y., Nguyen, D.V., Wong, H., Whelan, A.M., Zukin, R.S., Klann, E., and Tassone, F. (2012) Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 11: 332-341.Chévere-Torres, I., Kaphzan, H., Bhattacharya, A., Kang, A., Maki, J.M., Gambello, M.J., Arbiser, J.L., Santini, E., and Klann, E. (2012) Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the DRG mouse model of tuberous sclerosis complex. Neurobiol. Dis. 45: 1101-1110.Chévere-Torres, I., Maki, J., Santini, E., and Klann, E. (2012) Impaired social interactions and motor learning in tuberous sclerosis complex model mice expressing a dominant/negative form of tuberin. Neurobiol. Dis. 45: 156-164.Connor, S.A., Hoeffer, C.A., Klann, E., and Nguyen, P.V. (2011) Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus. Learn. Mem. 18: 207-220.Suvrathan, A., Hoeffer, C.A., Wong, H., Klann, E., and Chattarji, S. (2010) Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome. Proc. Natl. Acad. Sci. USA 107: 11591-11596.Sharma, A., Hoeffer, C.A., Takayasu, Y., Miyawaki, T., McBride, S.M., Klann, E., and Zukin, R.S. (2010) Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30: 694-702.Zhang, J., Hou, L., Klann, E., and Nelson, D.L. (2009) Altered hippocampal synaptic plasticity in the Fmr1 gene family knockout mouse models. J. Neurophysiol. 101: 2572-2580.Hoeffer, C.A., Tang, W., Wong, H., Santillan, A., Patterson, R.J., Martinez, L.A., Tejada-Simon, M.V., Paylor, R., Hamilton, S.L., and Klann, E. (2008) Removal of FKBP12 enhances mTOR/Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60: 832-845.Hoeffer, C.A., Sachan, N., Dey, A., Wong, H., Patterson, R.J., Shelton, J.M., Richardson, J.A., Klann, E., and Rothermel, B.A. (2007) The Down syndrome critical region protein RCAN1 regulates LTP and memory via inhibition of phosphatase signaling. J. Neurosci. 27: 13161-13172.