Jason Shepherd

Jason Shepherd, PhD

Languages spoken: English

Academic Information

Departments Adjunct - Biochemistry , Adjunct - Ophthalmology & Visual Sciences , Primary - Neurobiology

Lab

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

Education History

Other Training Intercultural Exchange in Switzerland, Kantonschule Trogen
Undergraduate University of Otago
 BS
Graduate Training University of California, Irvine
Doctoral Training The Johns Hopkins School of Medicine
 PhD
Postdoctoral Fellowship Howard Hughes Medical Institute
 Postdoctoral Fellow
Postdoctoral Fellowship The Picower Institute for Learning and Memory, Massachusetts Institute of Technology
 Postdoctoral Fellow

Selected Publications

Journal Article

  1. Day C, Shepherd JD (2015). Arc: building a bridge from viruses to memory. Biochem J, 469(1), e1-3.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Shepherd J (2012). Memory, plasticity and sleep - A role for calcium permeable AMPA receptors?. Frontiers in molecular neuroscience, 5, 49.
  15. Pastuzyn ED, Shepherd J (2017). Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome. Frontiers in molecular neuroscience, 10, 234.
  16. Ravens A, Stacher-Hörndli CN, Emery J, Steinwand S, Shepherd JD, Gregg (2023). Arc regulates a second-guessing cognitive bias during naturalistic foraging through effects on discrete behavior modules. iScience, 26(5), 106761.
  17. Bae D, Jones RE, Piscopo KM, Tyagi M, Shepherd JD, Hollien (2022). Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates. Molecular biology of the cell, 33(13), ar125.
  18. Kyrke-Smith M, Volk LJ, Cooke SF, Bear MF, Huganir RL, Shepherd J (2021). The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation. The Journal of neuroscience, 41(19), 4202-4211.
  19. Beagan JA, Pastuzyn ED, Fernandez LR, Guo MH, Feng K, Titus KR, Chandrashekar H, Shepherd JD, Phillips-Cremins J (2020). Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression. Nature neuroscience, 23(6), 707-717.
  20. Regier MJ, Shepherd J (2020). Expanding the AtLAS of non-coding RNA functions in the brain. Cell research, 30(4), 283-284.
  21. Jenks KR, Shepherd J (2020). Experience-Dependent Development and Maintenance of Binocular Neurons in the Mouse Visual Cortex. Cell reports, 30(6), 1982-1994.e4.
  22. Erlendsson S, Morado DR, Cullen HB, Feschotte C, Shepherd JD, Briggs JA (2020). Structures of virus-like capsids formed by the Drosophila neuronal Arc proteins. Nature neuroscience, 23(2), 172-175.
  23. Brown DG, Soto R, Yandamuri S, Stone C, Dickey L, Gomes-Neto JC, Pastuzyn ED, Bell R, Petersen C, Buhrke K, Fujinami RS, O'Connell RM, Stephens WZ, Shepherd JD, Lane TE, Round J (2019). The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling. eLife, 8,

Review

  1. Shepherd JD, Huganir RL (2007). The cell biology of synaptic plasticity: AMPA receptor trafficking. [Review]. Annu Rev Cell Dev Biol, 23, 613-43.
  2. Shepherd JD (2018). Arc - An endogenous neuronal retrovirus? [Review]. Semin Cell Dev Biol, 77, 73-78.
  3. Shepherd JD, Bear MF (2011). New views of Arc, a master regulator of synaptic plasticity. [Review]. Nat Neurosci, 14, (3), 279-84.
  4. Hantak MP, Einstein J, Kearns RB, Shepherd J (2021). Intercellular Communication in the Nervous System Goes Viral. Trends in neurosciences, 44(4), 248-259.

Other

  1. Xu J, Erlendsson S, Singh M, Regier M, Ibiricu I, Day GS, Piquet AL, Clardy SL, Feschotte C, Briggs JAG, Shepherd J (2023). PNMA2 forms non-enveloped virus-like capsids that trigger paraneoplastic neurological syndrome.