Scripps Research Logo

Peter Vanderklish, Ph.D.

Associate Professor
Department of Molecular Medicine
California Campus
Scripps VIVO Scientific Profile
pvanderk@scripps.edu
(858) 784-2624

Research Focus

Molecular mechanisms of functional and structural plasticity of glutamatergic synapses

          Our lab has a long standing interest in how local regulation of translation contributes to synaptic plasticity, and how dysfunctions in this key step in gene expression give rise to intellectual disability (Fragile X syndrome, FXS) and autism.  Our current efforts in this area (funded by the FRAXA Research Foundation) relate to the characterization of novel molecular signaling abnormalities in FXS that result from abnormal translational regulation, and testing whether their normalization by pharmacological approaches rescues various behavioral phenotypes in the Fmr1 knockout (KO) mouse model of FXS.  Guided in part by proteomic surveys we conducted in collaboration with Dr. Lujian Liao on cortical synapses from the Fmr1 KO mouse, these projects focus on specific changes in the Corticotropin Releasing Factor (CRF) and ADP ribosylation factor 6 (Arf6) signaling pathways.  In collaborative work with Dr.s Walter Francesconi, we determined that large changes in CRF signaling within the extended amygdala may alter synaptic properties in a manner that predisposes to a “high anxiety” set point in FXS that is not unlike what is seen in PTSD.  Chronic, severe anxiety (especially in the social domain) is one of the most burdensome and hard to treat aspects of FXS.  With regard to the Arf6 pathway, we are assessing whether upstream regulators of Arf6 serve as good points for therapeutic intervention to correct abnormalities in synaptic plasticity and behavior in the Fmr1 KO mouse.

          Another major effort in our lab centers on the molecular and cellular functions of the RNA-binding motif protein 3, a member of a small family of RNA-binding proteins that are induced by mild hypothermia and other physiological / metabolic stressors.  RBM3 exerts strong cellular protective functions and is the only protein upregulated in all cells during hibernation, suggesting a fundamental role in adaptive responses to metabolic stress.  In studies presently funded by NIAID, we are characterizing the role of RBM3 in type II innate lymphoid cells as a regulator of proinflammatory cytokine synthesis in the context of allergy.  In prior work, we found that RBM3 enhances global translation and dephosphorylation of eIF2alpha (part of the unfolded protein response).  Moreover, we discovered that RBM3 potently stimulates the biogenesis of a large set of microRNAs at the Dicer step.  These results suggested that one of the ways in which RBM3 confers cellular protection is by exerting largely anabolic effects on the proteome that are simultaneously sculpted via the microRNA pathway.  We are presently characterizing which of the multiple signaling effects of RBM3 are most important for its ability to confer cell protection in the context of muscle and brain.  In addition, we are evaluating whether pharmacological regulation of RBM3 can be leveraged to enhance the viability of neurons and synaptic connections

Education

Ph.D., Neurobiology, University of California, Irvine, 1997

Professional Experience

2013-2017 Associate Professor, Cell and Molecular Biology (CMB), The Scripps Research Institute
1997-2012 Assistant Professor, Neurobiology, The Scripps Research Institute

Awards & Professional Activities

2015-2019: NIH/NIAID, Research Protject Grant (R01, subaward)
2016-2017: FRAXA Research Foundation Grant
2009-2013: NIH/NINDS, Research Project Grant (R01)
2008-2010: The Del E. Webb Foundation Grant
2004-2008: FRAXA Research Foundation Grant
2001-2004: NIH/NIMH, Mentored Research Scientist Development Award (K01)

Selected References

All Publications

Tang B, Wang T, Wan H, Han L, Qin X, Zhang Y, Wang J, Yu C, Berton F, Francesconi W, Yates JR 3rd, Vanderklish PW, Liao L. Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome. Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):E4697-706. PMID: 26307763 PMCID: PMC4553823. 

Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, Warren ST, Vanderklish PW, Kind PC, Carpenter RL, Bear MF, Healy AM. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABA(B) receptors with arbaclofen.  Sci Transl Med. 2012 Sep 19;4(152):152ra128.

Liao L, Sando RC, Farnum JB, Vanderklish PW, Maximov A, Yates JR.  15N-labeled brain enables quantification of proteome and phosphoproteome in cultured primary neurons. J Proteome Res. 2012 Feb 3;11(2):1341-53.

Pilotte J, Dupont-Versteegden EE, Vanderklish PW. Widespread regulation of miRNA biogenesis at the Dicer step by the cold-inducible RNA-binding protein, RBM3.  PLoS One. 2011;6(12):e28446.

Ferry AL, Vanderklish PW, Dupont-Versteegden EE.  Enhanced survival of skeletal muscle myoblasts in response to overexpression of cold shock protein RBM3.  Am J Physiol Cell Physiol. 2011 Aug;301(2):C392-402.

Pilotte J, Cunningham BA, Edelman GM, Vanderklish PW. Developmentally regulated expression of the cold-inducible RNA-binding motif protein 3 in euthermic rat brain. Brain Res. 2009 Mar 3;1258:12-24. 

Liao L, Park SK, Xu T, Vanderklish P, Yates JR 3rd. Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15281-6

Liao, L., Pilotte, J., Xu, T., Wong, C.C., Edelman, G.M., Vanderklish, P., Yates, J.R. 3rd  BDNF induces widespread changes in synaptic protein content and up-regulates components of the translation machinery: an analysis using high-throughput proteomics. J. Proteome Res. (2007) 6: 1059-1071

Vanderklish, P.W. and Edelman, G.M.  Differential Translation and Fragile X Syndrome.  Genes, Brain, Behav. (2005).  6: 360-384

Aschrafi, A., Cunningham, B.A., Edelman, G.M., Vanderklish, P.W.  The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain.  Proc. Natl. Acad. Sci. USA (2005). 102: 2180-2185.

Desai N.S., Casimiro T.M., Gruber S.M., Vanderklish P.W.  Early postnatal plasticity in neocortex of Fmr1 knockout mice. J Neurophysiol. (2006); 96:1734-1745.

Smart, F.M., Edelman, G.M., and Vanderklish, P.W. BDNF induces translocation of initiation factor 4E to mRNA granules: Evidence for a role of synaptic microfilaments and integrins.  Proc. Natl. Acad. Sci. USA (2003). 100: 14403-14408.

Vanderklish, P.W., and Edelman, G.M. Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA (2002). 99: 1639-1644.

Yin, Y., Edelman, G.M., and Vanderklish, P.W. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc. Natl. Acad. Sci. USA (2002). 99: 2368-2373.

Vanderklish P.W., Krushel L.A., Holst B.H., Gally J.A., Crossin K.L., Edelman G.M. Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer. Proc. Natl. Acad. Sci. USA (2000). 97: 2253-2258.

Vanderklish, P.W., and Edelman, G.M. Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons. Proc. Natl. Acad. Sci. USA (2002). 99: 1639-1644.

Vanderklish, P.W., Bahr, B.A., (Review) The pathogenic activation of calpain: a marker and mediator of cellular toxic states. Int. J. Exp. Pathol. (2000). 81: p. 323-339

Lauterborn J.C., Lynch G., Vanderklish P., Arai A., Gall C.M., Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J. Neurosci. (2000). 20: 8-21.

Vanderklish, P., Bednarski E., Lynch G. Translational suppression of calpain blocks long-term potentiation. Learn. Mem. (1996). 3: 209-217.

Vanderklish, P.W., Neve, R., Bahr, B.A., Arai, A., Hennegriff, M., Larson, J., Lynch, G., Translational suppression of a glutamate receptor subunit impairs long-term potentiation. Synapse (1992). 12: 333-337.

Vanderklish, P., Saido, T.C., Gall, C., Arai, A., Lynch, G., Proteolysis of spectrin by calpain accompanies theta-burst stimulation in cultured hippocampal slices. Mol. Brain Res. (1995). 32: 25-35.

Staubli, U., Vanderklish, P.W., Lynch, G., An inhibitor of integrin receptors blocks long-term potentiation. Behav. Neural Biol. (1990). 53: 1-5.

Lee, K.S., Frank, S., Vanderklish, P.W., Arai, A., Lynch, G., Inhibition of proteolysis protects hippocampal neruons from ischemia. Proc. Natl. Acad. Sci. USA (1991). 88: 7233-7237.