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Pathophysiology of genetically defined developmental brain disorders

Ongoing projects are addressing the following questions:

• What are the molecular mechanisms that couple mGluR5 to protein synthesis, and do these represent novel therapeutic targets for FX?

• What proteins are overexpressed in FX, and how do they contribute to LTD and pathophysiology of the disease?

• Can adult onset treatments reverse damage caused by altered brain development in fragile X?

• Can a “high content” assay of cultured neurons from the Fmr1 KO mouse be used to screen chemical libraries for novel therapeutics?

• Do other single gene disorders characterized by intellectual disability and autism share the same synaptic pathophysiology as fragile X?  Current efforts are focused on the Tsc2+/- mouse model of tuberous sclerosis, and the MeCP2 null model of Rett syndrome.

Sample of relevant recent papers:

Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RK, Bear MF
Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile x syndrome
Neuron. 2013 Jan 23;77(2):243-50

Bhakar AL, Dölen G, Bear MF
The pathophysiology of fragile X (and what it teaches us about synapses)
Annu Rev Neurosci. 2012;35:417-43

Zoghbi HY, Bear MF
Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities
Cold Spring Harb Perspect Biol. 2012 Mar 1;4(3). Review

Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L
Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice
Neuron. 2012 Apr 12;74(1):49-56

Auerbach BD, Osterweil EK, Bear MF
Mutations causing syndromic autism define an axis of synaptic pathophysiology
Nature. 2011 Nov 23;480(7375):63-68

Krueger DD, Bear MF
Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome
Annu Rev Med. 2011;62:411-29

Krueger DD, Osterweil EK, Chen SP, Tye LD, Bear MF
Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2587-92

Osterweil EK, Krueger DD, Reinhold K, Bear MF
Hypersensitivity to mGluR5 and ERK1/2 Leads to Excessive Protein Synthesis in the Hippocampus of a Mouse Model of Fragile X Syndrome
J Neurosci. 2010 Nov 17;30(46):15616-27

Krueger DD, Osterweil EK, Bear MF
Activation of mGluR5 induces rapid and long-lasting protein kinase D phosphorylation in hippocampal neurons

J Mol Neurosci. 2010 Sep;42(1):1-8. Epub 2010 Feb 23

Auerbach BD, Bear MF
Loss of the fragile X mental retardation protein decouples metabotropic glutamate receptor dependent priming of long-term potentiation from protein synthesis
J Neurophysiol. 2010 Aug;104(2):1047-51

Dölen G, Bear MF
Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome
J Physiol. 2008 Mar 15;586(6):1503-8

Hung AY, Futai K, Sala C, Valtschanoff JG, Ryu J, Woodworth MA, Kidd FL, Sung CC, 
Miyakawa T, Bear MF, Weinberg RJ, Sheng M
Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1
J Neurosci. 2008 Feb 13;28(7):1697-708

Kelleher RJ 3rd, Bear MF
The autistic neuron: troubled translation?
Cell. 2008 Oct 31;135(3):401-6

Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF.
Correction of fragile X syndrome in mice
Neuron. 2007 Dec 20;56(6):955-62