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.
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
The Picower Institute for Learning and Memory, Massachusetts Institute of Technology
Howard Hughes Medical Institute
The Johns Hopkins School of Medicine
University of California, Irvine
University of Otago
Intercultural Exchange in Switzerland, Kantonschule Trogen
- Ravens A, Stacher-Hrndli CN, Emery J, Steinwand S, Shepherd JD, Gregg C (2023). Arc regulates a second-guessing cognitive bias during naturalistic foraging through effects on discrete behavior modules. iScience, 26(5), 106761.
- Bae D, Jones RE, Piscopo KM, Tyagi M, Shepherd JD, Hollien J (2022). Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates. Mol Biol Cell, 33(13), ar125.
- Kyrke-Smith M, Volk LJ, Cooke SF, Bear MF, Huganir RL, Shepherd JD (2021). The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation. J Neurosci, 41(19), 4202-4211.
- Beagan JA, Pastuzyn ED, Fernandez LR, Guo MH, Feng K, Titus KR, Chandrashekar H, Shepherd JD, Phillips-Cremins JE (2020). Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression. Nat Neurosci, 23(6), 707-717.
- Regier MJ, Shepherd JD (2020). Expanding the AtLAS of non-coding RNA functions in the brain. Cell Res, 30(4), 283-284.
- Jenks KR, Shepherd JD (2019). Experience-Dependent Development and Maintenance of Binocular Neurons in the Mouse Visual Cortex. Cell Rep, 30(6), 1982-1994.e4.
- Erlendsson S, Morado DR, Cullen HB, Feschotte C, Shepherd JD, Briggs JAG (2020). Structures of virus-like capsids formed by the Drosophila neuronal Arc proteins. Nat Neurosci, 23(2), 172-175.
- Brown DG, Soto R, Yandamuri S, Stone C, Dickey L, Gomes-Neto JC, Pastuzyn ED, Bell R, Petersen C, Buhrke K, Fujinami RS, OConnell RM, Stephens WZ, Shepherd JD, Lane TE, Round JL (2019). The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling. Elife, 8.
- Eavri R, Shepherd J, Welsh CA, Flanders GH, Bear MF, Nedivi E (2018). Interneuron Simplification and Loss of Structural Plasticity As Markers of Aging-Related Functional Decline. J Neurosci, 38(39), 8421-8432.
- Wall MJ, Collins DR, Chery SL, Allen ZD, Pastuzyn ED, George AJ, Nikolova VD, Moy SS, Philpot BD, Shepherd JD, Muller J, Ehlers MD, Mabb AM, Correa SAL (2018). The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility. Neuron, 98(6), 1124-1132.e7.
- Pastuzyn ED, Day CE, Kearns RB, Kyrke-Smith M, Taibi AV, McCormick J, Yoder N, Belnap DM, Erlendsson S, Morado DR, Briggs JAG, Feschotte C, Shepherd JD (2018). The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Intercellular RNA Transfer. Cell, 172(1-2), 275-288.e18.
- Jenks KR, Kim T, Pastuzyn ED, Okuno H, Taibi AV, Bito H, Bear MF, Shepherd JD (2017). Arc restores juvenile plasticity in adult mouse visual cortex. Proc Natl Acad Sci U S A, 114(34), 9182-9187.
- Pastuzyn ED, Shepherd JD (2017). Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome. Front Mol Neurosci, 10, 234.
- Day C, Shepherd JD (2015). Arc: building a bridge from viruses to memory. Biochem J, 469(1), e1-3.
- Gee JM, Smith NA, Fernandez FR, Economo MN, Brunert D, Rothermel M, Morris SC, Talbot A, Palumbos S, Ichida JM, Shepherd JD, West PJ, Wachowiak M, Capecchi MR, Wilcox KS, White JA, Tvrdik P (2014). Imaging activity in neurons and glia with a Polr2a-based and cre-dependent GCaMP5G-IRES-tdTomato reporter mouse. Neuron, 83(5), 1058-72.
- Shepherd JD (2012). Memory, plasticity and sleep - A role for calcium permeable AMPA receptors? Front Mol Neurosci, 5, 49.
- Wu J, Petralia RS, Kurushima H, Patel H, Jung MY, Volk L, Chowdhury S, Shepherd JD, Dehoff M, Li Y, Kuhl D, Huganir RL, Price DL, Scannevin R, Troncoso JC, Wong PC, Worley PF (2011). Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent beta-amyloid generation. Cell, 147(3), 615-28.
- Smith-Hicks C, Xiao B, Deng R, Ji Y, Zhao X, Shepherd JD, Posern G, Kuhl D, Huganir RL, Ginty DD, Worley PF, Linden DJ (2010). SRF binding to SRE 6.9 in the Arc promoter is essential for LTD in cultured Purkinje cells. Nat Neurosci, 13(9), 1082-9.
- McCurry CL, Shepherd JD, Tropea D, Wang KH, Bear MF, Sur M (2010). Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation. Nat Neurosci, 13(4), 450-7.
- Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, Chowdhury S, Kaufmann W, Kuhl D, Ryazanov AG, Huganir RL, Linden DJ, Worley PF (2008). Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron, 59(1), 70-83.
- Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, Huganir RL, Worley PF (2006). Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron, 52(3), 475-84.
- Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF (2006). Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron, 52(3), 445-59.
- Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003). Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron, 39(3), 409-21.
- Hantak MP, Einstein J, Kearns RB, Shepherd JD (2021). Intercellular Communication in the Nervous System Goes Viral. [Review]. Trends Neurosci, 44(4), 248-259.
- Shepherd JD (2018). Arc - An endogenous neuronal retrovirus? [Review]. Semin Cell Dev Biol, 77, 73-78.
- Shepherd JD, Bear MF (2011). New views of Arc, a master regulator of synaptic plasticity. [Review]. Nat Neurosci, 14(3), 279-84.
- Shepherd JD, Huganir RL (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. [Review]. Annu Rev Cell Dev Biol, 23, 613-43.
- Xu J, Erlendsson S, Singh M, Regier M, Ibiricu I, Day GS, Piquet AL, Clardy SL, Feschotte C, Briggs JAG, Shepherd JD (2023). PNMA2 forms non-enveloped virus-like capsids that trigger paraneoplastic neurological syndrome. United States.
- MALONE, Colin LAPTENKO, Oleg FRAITES, Adam CRISP, Jessica PISAREV, Andrey ANGAD, Anil ONG, Heley GILBERT, Zachary SHEPHERD, Jason D. (2022). PNMA2-BASED CAPSIDS AND USES THEREOF. U.S. Patent No. 013954. Washington, D.C.:U.S. Patent and Trademark Office.
- Jason Shepherd, Cameron Day, Elissa Pastuzyn (2018). Compositions and Methods of Use of Arc Capsids. U.S. Patent No. 543130. Washington, D.C.:U.S. Patent and Trademark Office.