Associate Professor of Neurobiology, Adjunct Associate Professor of Biochemistry,
and Adjunct Associate Professor of
Ophthalmology and Visual Sciences
Jon M. Huntsman Presidential Endowed Chair
Synaptic Plasticity, Memory and Neurological Disorders, Memory Formation
Molecular Biology Program
Biological Chemistry Program
B.Sc. (Hons) University of Otago, Dunedin, New Zealand
Ph.D. Johns Hopkins University
Brains have an amazing ability to learn and store information for long periods - in some cases, a lifetime. A major challenge in neuroscience is to understand how neuronal networks are sculpted by experience and how proteins/genes contribute to circuit modification. The goal of our research is to understand information storage, from the molecular level through in vivo neuronal networks and how these processes go awry in neurological disorders. My lab utilizes coordinated biochemical, cell biological, electrophysiological and imaging studies both in vitro and in vivo.
We recently discovered a novel mechanism of neuronal communication that resembles the life-cycle of retroviruses (https://www.sciencedirect.com/science/article/pii/S0092867417315040) . The neuronal gene Arc, a master regulator of synaptic plasticity and memory, contains a Gag retroviral homology domain that has conserved secondary structure with HIV-1 that is derived from a distinct family of retrotransposons. Arc protein self-assembles into viral-like capsids that are released from cells and carry RNA/proteins to neighboring cells. Our findings open up a new area of investigation in the cell biology of cell-to-cell communication, by revealing that some retrotransposon-derived genes retain the ability to form capsids that shuttle RNAs and proteins between cells. Ongoing projects in the lab aim to dissect this new intercellular pathway that intersects diverse fields of biology that include virology, extracellular communication, evolutionary biology, gene delivery and neuroscience.
Other projects in the lab include:
- The synaptic engram - how networks of cells encode, store and retrieve information
- How experience sculpts the brain, using in vivo 2-photon imaging in the visual cortex
- The synaptic dysfunction that underlies neurological disorders, including Alzheimer's Disease and autism spectrum disorders
- Trafficking of neurotransmitter receptors at synapses
References (Selected Publications)
- Hantak M.P., Einstein J., Kearns R.B., Shepherd J.D. Intercellular Communication in the Nervous System Goes Viral. Trends Neurosci, 2021 Apr;44(4):248-259.
- Beagan J.A., Pastuzyn E.D., Fernandez L.R., Titus K.R., Chandrashekar H., Shepherd J.D.*, Phillips-Cremins J.E.*. Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression.Nature Neuroscience, In Press.
- Regier M.J., and Shepherd J.D. Expanding the AtLAS of non-coding RNA functions in the brain. Cell Research, 2020 April;30(4):283-284.
- Jenks K.R., and Shepherd J.D. Experience-dependent development and maintenance of binocular neurons in the mouse visual cortex. Cell Reports, 2020 Feb 11;30(6):1982-1994.e4.
- Erlendsson S., Murado D.R., Harrison B. Cullen , Cedric Feschotte, Shepherd J.D.,. Briggs J.A.G.Structures of virus-like capsids formed by the Drosophila neuronal Arc proteins. Nature Neuroscience, 2020 Feb;23(2):172-175.
- Soto R., D. Brown G., Worne C, Pastuzyn E.D., Bell R., Petersen C., Buhrke K., Fujinami R.,. O’Connell R.M., Stephens W.Z., Shepherd J.D., Lane T.E. and Round J.L.. Early life exposure to gut bacterial products prime microglia to protect from viral-induced neurologic disease. eLife, 2019 July 16;8. pii: e47117.
- Shepherd J.D. Deconstructing the Synapse. Nature Neuroscience. 2018 Oct;21(10):1294-1295.
- Wall M.J., Collins D.R., Chery S.L., Allen Z.D., Pastuzyn E.D., Nikolova V.D., Moy S.S., Philpot B.D., Shepherd J.D., Müller J., Ehlers M.D., Mabb A.M., Corrêa S.A.L. The temporal dynamics of Arc expression regulates cognitive flexibility. Neuron,2018 May 24. pii: S0896-6273(18)30384-2
- Shepherd J.D. Arc - An endogenous neuronal retrovirus? Seminars in Cell & Developmental Biology. 2018 May;77:73-78. Epub 2017 Sep 24.
- Pastuzyn E.D., Day C.E., Kearns R.B., Kyrke-Smith M., Taibi A.V., McCormick J., Belnap D.M., Yoder N., Erlendsson S., Morado D.R., Briggs J.A.G., Feschotte C. and Shepherd J.D. The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer. Cell,2018 Jan 11;172(1-2):275-288.e18.
- Jenks K.R., Kim T., Pastuzyn E.D., Okuno H., Taibi A.V., Bito H., Bear M.F., Shepherd J.D. Arc restores juvenile plasticity in adult mouse visual cortex.PNAS, 2017 Aug 22;114(34):9182-9187.
- Pastuzyn E.D. and Shepherd J.D. Arc-dependent Homeostatic Synaptic Plasticity Is Altered in Angelman Syndrome Model Mice. Frontiers in Molecular Neuroscience, 2017 Jul 28;10:234.
- Wu J., Petralia R.S., Kurushima H., Patel H., Jung M., Volk L., Chowdhury S.,Shepherd J.D., Dehoff M., Li Y., Kuhl D., Huganir R.L., Price D.L., Scannevin R., Troncoso J.C., Wong P.C., Worley P.F. Arc/Arg3.1 Regulates an Endosomal Pathway Essential for Activity-Dependent β-Amyloid Generation. Cell. 2011 Oct 27;147(3):615-628.
- Shepherd J.D and Bear M.F. New views of Arc, a master regulator of synaptic plasticity. Nature Neuroscience. 2011 March; 14(3): 279–284.
- McCurry C*., Shepherd J.D.*, Tropea D., Wang K., Bear M.F., Sur M.Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation. Nature Neuroscience. 2010 Apr;13(4):450-7.
- Park S., Park J.M., Kim S., Kim J.A., Shepherd J.D., Smith-Hicks C.L., Chowdhury S., Kaufmann W., Kuhl D., Ryazanov A.G., Huganir R.L., Linden D.J., Worley P.F. (2008). Eukaryotic elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc essential for mGluR-LTD. Neuron 2008 Jul 10;59(1):70-83.
- Shepherd J.D., Huganir R.L. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annual Review of Cell and Developmental Biology. 2007 Nov Vol. 23: 613-643.
- Shepherd J.D.*, Rumbaugh G.*, Wu J. Chowdhury S., Plath N., Kuhl D., Huganir R.L., Worley P.F. Arc/Arg3.1 Mediates synaptic scaling of AMPA receptors. Neuron. 2006 Nov 9;52(3):475-84.
- Chowdhury S.* Shepherd J.D.*, Ojuno H., Lyford G.,Petralia R., Plath N., Kuhl D., Huganir R.L., Worley P.F. Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron. 2006 Nov 9;52(3):445-59.