Jeffrey D. Erickson, Ph.D.
Jeffrey D. Erickson, Ph.D.
Professor of Neuroscience, Pharmacology and Experimental Therapeutics
Professor of Neuroscience, Pharmacology and Experimental Therapeutics
Neuroscience Center of Excellence
School of Medicine, LSU Health
2020 Gravier St.
New Orleans, LA 70112
Phone: (504) 599-0845
Fax: (504) 599-0488
Neuroscience Center of Excellence
1992: Ph.D. (Genetics), George Washington University, Washington, DC
1984: M.Sc. (Pharmaceutical Sciences), University of Colorado, Boulder, CO
1981: B.A. (Molecular, Cellular, and Developmental Biology), University of Colorado, Boulder, CO
2021 - Present: Professor of Pharmacology and Neuroscience, Neuroscience Center of Excellence, LSU Health Sciences Center, New Orleans, LA.
2002 - 2021: Associate Professor of Pharmacology and Neuroscience, Neuroscience Center of Excellence, LSU Health Sciences Center, New Orleans, LA
1997 - 2002: Assistant Professor of Pharmacology and Neuroscience, Neuroscience Center of Excellence, LSU Health Sciences Center, New Orleans, LA
1993 - 1997: Postdoc, Laboratory of Cell Biology, NIMH, Bethesda, MD
synaptic vesicle transporter proteins, neuronal glutamine transporters,
molecular and cellular biology of vesicular neurotransmitter transporters
A. Vesicular glutamate transporters in the regulation of glutamate release
Presynaptic mechanisms that contribute to quantal variance and synaptic plasticity are poorly understood. It has been established that, for mammalian cortical glutamatergic synaptic vesicles that express VGLUT1, quantal size is determined by the number of transporters per vesicle, and that this density is endogenously regulated both across development and by prolonged changes in activity of mature neural networks. Furthermore, VGLUT1 and VGAT are oppositely (and bi-directionally) regulated by prolonged changes in neural activity in vitro. This indicates that mechanisms of synaptic scaling (i.e., homeostatic plasticity include regulation of vesicle filling with glutamate and GABA in a manner that serves to restore excitatory/inhibitory balance. We have also shown that VGLUT1 plays an unanticipated role in synapses; it interacts with adaptor proteins such as endophilin A1 within axonal boutons that alter the availability of excitatory vesicles for release, at least compared to VGLUT2 or VGLUT3. Our prior research focused on the differential role for VGLUT1 and VGLUT2 isoforms in corticolimbic circuitry during the maturation of synaptic connectivity and plasticity in vitro and in vivo.
B. The role of neuronal glutamine transporters in glutamatergic neurotransmission
Excessive presynaptic glutamatergic transmission is thought to be involved in various human disorders including epilepsy that result in neuronal excitotoxicity. Glutamatergic transmission requires the transport of cytoplasmic glutamate into synaptic vesicles prior to release from axon terminals by Ca 2+ -dependent exocytosis. Under normal conditions, Krebs cycle intermediates such as alpha-ketoglutarate can sustain axon terminal cytoplasmic glutamate levels and neurotransmitter glutamate stores. However, seizures or intense glutamatergic activity requires import of Gln into axon terminals from glia to immediately replenish and maintain vesicular glutamate stores for continued release. Importantly, this ‘so called’ glutamate/Gln cycle, proposed over 35 years ago from classic biochemical and immunological evidence, is an accepted model of neurotransmitter glutamate recycling and is presented as such in most neuroscience texts on this subject. However, while the transporters that mediate Gln efflux from astrocytes are known (SNAT3 and SNAT5), the neuronal Gln transporter that mediates Gln transport into presynaptic nerve terminals has not yet been identified. Interestingly, activity-induced modulation of synaptic efficacy and glutamatergic epileptiform activity is significantly reduced by application of 2-(methylamino)isobutyrate (MeAIB), a competitive and reversible inhibitor of the sodium-coupled neutral amino acid transporter (SNAT; system A) subtypes 1 and 2. We were the first to clone and functionally identify the Slc38 gene family members SNAT1 and SNAT2 and have since documented that these two Gln transporters are excluded from axon terminals, suggesting that an unidentified neuronal Gln transporter sustains glutamatergic transmission under seizure-like activity.
We have recently functionally identified an activity regulated MeAIB/Gln transport system in neuron-enriched hippocampal cultures that is inhibited by riluzole, an anticonvulsant agent that reduces synaptic release of Glu. We screened two riluzole based libraries to identify compounds that possess the ability to inhibit spontaneous neural activity regulated, high affinity MeAIB/Gln transport as potently as riluzole, but are structurally unique. Based upon these screens, we have synthesized several novel chlorinated naphthalenyl substituted aminothiazoles (e.g., SKA-378) that also potently inhibit activity regulated MeAIB transport at the plasma membrane in vitro and that exhibit excellent 'drug-like' properties with high oral availability and good brain penetration. We tested whether riluzole and these novel compounds could prevent acute neural excitotoxic injury in a rat model of temporal lobe epilepsy. While SKA-378 could not prevent seizure activity both riluzole and SKA-378 prevent acute neural injury following kainic acid induced status epilepticus. Our goal is to understand mechanisms involved in the progression of epileptic disease following epileptogenic seizures.
Kyllo, T., Singh, V., Shim, H., Latika, S., Nguyen, H.M., Chen, Y.-J., Terry, E., Wulff, H., and Erickson, J.D. (2023) Riluzole and novel naphthalenyl substituted aminothiazole derivatives prevent acute neural excitotoxic injury in a rat model of temporal lobe epilepsy. Neuropharmacology 224:109349.
Pietrancosta, N., Djibo, M., Daumas, S., El Mestikawy, S., and Erickson, J.D. (2020) Molecular, structural, functional, and pharmacologic sites for vesicular glutamate transporter regulation. Mol. Neurobiol. 57: 3118-3142.
Erickson, J.D. (2017) Functional identification of activity-regulated, high-affinity glutamine transport in hippocampal neurons inhibited by riluzole. J.Neurochem. 142: 29-40.
- Jin, L.W., Horiuchi, M., Wulff, H., Liu, X.B., Cortopassi, G.A., Erickson, J.D., and Maezawa, I. (2015) Dysregulation of glutamine transporter SNAT1 in Rett Syndrome microglia: A mechanism for mitochondrial dysfunction and neurotoxicity. J. Neurosci. 35: 2516-2529.
- He, H., Mahnke, A.E., Doyle, S., Fan, N., Wang, C.C., Hall, B.J., Tang, Y.P., Inglis, F.M., Chen, C., and Erickson, J.D. (2012) Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning. J. Neurosci. 32:(45):15886-15901.
- Doyle, S., Pyndiah, S., De Gois S., and Erickson, J.D. (2010) Excitation-transcription coupling via calcium/calmodulin-dependent protein kinase/ERK1/2 signaling mediates the coordinate induction of VGLUT2 and Narp triggered by a prolonged increase in glutamatergic synaptic activity. J. Biol. Chem. 285:14366-14376.
- Grewal, S., Defamie, N., Zhang, X., De Gois, S., Shawki, A., Mackenzie, B., Chen, C., Varoqui, H., and Erickson, J.D. (2009) SNAT2 amino acid transporter is regulated by amino acids of the SLC6 GABA transporter subfamily in neocortical neurons and may play no role in delivering glutamine for glutamatergic transmission. J. Biol. Chem. 284:11224-11236.
- Ernst, C., Dumoulin, P., Cabot, S., Erickson, J.D., and Turecki, G. (2009) SNAT1 and a family with high rates of suicidal behavior. Neuroscience 162: 415-422.
- Evans, K., Nasim, Z., Brown, J., Butler, H., Kauser, S., Varoqui, H., Erickson, J.D., Herbert, T.P., and Bevington, A. (2007) Acidosis-sensing glutamine pump SNAT2 determines amino acid levels and mammalian target of rapamycin signaling to protein synthesis in L6 muscle cells. J. Am. Soc. Nephrol. 18: 1426-1436.
- Burkhalter, J., Fiumelli, H., Erickson, J.D., and Martin, J.L. (2007) A critical role for system A amino acid transport in the regulation of dendritic development by BDNF. J. Biol. Chem. 282: 5152-5159.
- De Gois, S., Jeanclos, E., Morris, M., Grewal, S., Varoqui, H., and Erickson, J.D. (2006) Identification of endophilins 1 and 3 as selective binding partners for VGLUT1 and their co-localization in neocortical glutamatergic synapses: implications for vesicular glutamate transporter trafficking and excitatory vesicle formation. Cell. Mol. Neurobiol. 26:679-693.
Erickson, J.D., De Gois, S., Varoqui, H., Schafer, M.K., and Weihe, E. (2006) Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size. Neurochem. Int. 48:643-649.
- Melone, M., Varoqui, H., Erickson, J.D., and Conti, F. (2006) Localization of the Na(+)-coupled neutral amino acid transporter 2 in the cerebral cortex. Neuroscience 140: 281-292.
- DeGois, S., Schafer, M.K.-H., Defamie, N., Ricci, A., Weihe, E., Varoqui, H., and Erickson, J.D. (2005) Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits. J. Neurosci. 25:7121-7133.
- Wilson, N.R., Kang, J., Hueske, E. V., Leung, T., Varoqui, H., Murnick, J. G., Erickson, J.D., and Liu, G. (2005) Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1. J. Neurosci. 25:6221-6234.
- Yao, J., Erickson, J.D., and Hersh, L.B. (2004) Protein kinase A affects trafficking of the vesicular monoamine transporters in PC12 cells. Traffic 5: 1006-1016.
- Melone, M., Quagliano, F., Barbaresi, P., Varoqui, H., Erickson, J.D., and Conti, F. (2004) Localization of the glutamine transporter SNAT1 in rat cerebral cortex and neighboring structures, with a note on its localization in human cortex. Cereb. Cortex14: 562-574.
- Atkinson, L., Batten T.F., Moores, T.S., Varoqui, H., Erickson, J.D., and Deuchars, J. (2004) Differential co-localisation of the P2X(7) receptor subunit with vesicular glutamate transporters VGLUT1 and VGLUT2 in rat CNS. Neuroscience 123, 761-768.
- Franchi-Gazzola, R., Gaccioli, F., Bevilacqua, E., Visigalli, R., Dall’Asta, V., Sala, R., Varoqui, H., Erickson, J.D., Gazzola, G.C., and Bussolati, O. (2004) The synthesis of SNAT2 transporters is required for the hypertonic stimulation of system A transport activity. Biochim. Biophys. Acta 1667, 157-166.
- Mackenzie, B., and Erickson, J.D. (2004) Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch. 447:784-795.
- Sindreu, C.B., Varoqui, H., Erickson, J.D., and Pérez-Clausell, J. (2003) Boutons containing vesicular zinc define a subpopulation of synapses with low AMPAR content in rat hippocampus. Cerebral Cortex 13, 823-829.
- Mackenzie, B., Schäfer, M.K.-H., Erickson, J.D., Hediger, M.A., Weihe, E., and Varoqui, H. (2003) Functional properties and cellular distribution of the system A glutamine transporter SNAT1 support specialized roles in central neurons.J. Biol. Chem. 278:23720-29730.
- Varoqui, H., and Erickson, J.D. (2002) Selective up-regulation of system A transporter mRNA in diabetic liver. Biochem. Biophys. Res. Comm. 290:903-908.
- Schäfer, M. K.-H., Varoqui, H., Weihe, E., and Erickson, J.D. (2002) Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons. J. Biol. Chem. 277:50734-50748.
- Varoqui, H., Schäfer, M.K.-H., Zhu, H., Weihe, E., and Erickson, J.D. (2002) Identification of the differentiation-associated Na+/Pi transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses. J. Neurosci. 22:142-155.
- Armano, S., Coco, S., Bacci, A., Pravettoni, E., Schenk, U., Verderio, C., Varoqui, H., Erickson, J.D., and Matteoli, M. (2002) Localization and functional relevance of system A neutral amino acid transporters in cultured hippocampal neurons. J. Biol. Chem. 277, 10467-10473.
- Jakobsen, A.-M., Andersson, P., Saglik, G., Andersson, E., Kölby, L., Erickson, J.D., Forssell-Aronsson, E., Wängberg, B. Hakan Ahlman, and Nilsson, O. (2001) Differential expression of vesicular monoamine transporter (VMAT) 1 and 2 in gastrointestinal endocrine tumours. J. Pathol. 195, 463-472.
- Zhu, H., Varoqui, H., Duerr, J., McManus, J.R., Rand, J., and Erickson, J.D. (2001) Analysis of unc-17 point mutants in Caenorhabditis elegans reveals domains of the vesicular acetylcholine transporter involved in substrate translocation. J. Biol. Chem. 276:41580-41587.
Erickson, J.D. and Varoqui, H. (2000) Molecular analysis of vesicular amine transporter function and targeting to secretory organelles. FASEB J. 14:2450-2458.
- Varoqui, H., Zhu, H., Yao, D., Ming, H., and Erickson, J.D. (2000) Cloning and functional identification of a neuronal glutamine transporter. J. Biol. Chem. 275:4049-4054.
- Yao, D., Mackenzie, B., Ming, H., Varoqui, H., Zhu, H., Hediger, M.A., and Erickson, J.D. (2000) A novel system A isoform mediating Na+/neutral amino acid cotransport. J. Biol. Chem. 275:22790-22797.
- Gilmor, M.L., Erickson, J.D., Varoqui, H., Hersh, L.B., Bennett, D., Cochran, L., Mufson, E.J., and Levey, A.I. (1999) Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer’s disease. J. Comp. Neurol. 411, 693-704.
- Miller, G.W., Erickson, J.D., Perez, J.T., Penland, S.N., Mash, D.C., Rye, D.B., and Levey, A.I. (1999) Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson’s disease. Exp. Neurol. 156, 138-148.
- Kölby, L., Wängberg, B., Ahlman, H., Jansson, S., Forssel-Aronsson, E., Erickson, J.D., and Nilsson, O. (1998) Gastric carcinoid with histamine production, histamine transporter and expression of somatostatin receptors. Digestion 59, 160-166.
- Varoqui, H. and Erickson, J.D. (1998) Dissociation of the vesicular acetylcholine transporter domains important for high-affinity transport recognition, vesamicol-binding and targeting to synaptic vesicles. J. Physiol. (Paris) 92, 141-144.
Erickson, J.D. (1998) A chimeric vesicular monoamine transporter dissociates sensitivity to tetrabenazine and unsubstituted aromatic amines. Adv. Pharmacol. 42, 227-232.
- Varoqui, H. and Erickson, J.D. (1998) The cytoplasmic tail of the vesicular acetylcholine transporter contains a synaptic vesicle-targeting signal. J. Biol. Chem. 273:9094-9098.
- Varoqui, H. and Erickson, J.D. (1998) Functional identification of vesicular monoamine and acetylcholine transporters. Methods Enzymol. 296:84-99.
- Varoqui, H. and Erickson, J.D. (1997) Vesicular neurotransmitter transporters: potential sites for the regulation of synaptic function. Mol. Neurobiol. 15:165-191.
Erickson, J.D., Schäfer, M. K.-H., Bonner, T.I., Eiden, L.E., and Weihe, E. (1996) Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc. Natl. Acad. Sci. 93:5166-5171.
- Weihe, E., Tao-Cheng, J.-H., Schäfer, M.K.-H., Erickson, J.D., and Eiden. L.E. (1996) Visualization of the vesicular acetylcholine transprter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles. Proc. Natl. Acad. Sci. 93, 3547-3552.
Erickson, J.D., Weihe, E., Schafer, M.K.-H., Neale, E., Williamson, L, Bonner, T.I., Tao-Cheng, J.H., and Eiden, L.E. (1996) The VAChT/ChAT “cholinergic gene locus”. New aspects of genetic and vesicular regulation of cholinergic function. Prog. Brain Res. 109, 69-82.
- Varoqui, H. and Erickson, J.D. (1996) Active transport of acetylcholine by the human vesicular acetylcholine transporter. J. Biol. Chem. 271:27229-27232.
- Usdin, T. B., Eiden, L. E., Bonner, T. I., and Erickson, J.D. (1995) Molecular biology of the vesicular ACh transporter. Trends in Neurosci. 18:218-224.
Erickson, J.D., Eiden, L.E., Schäfer, M.K.-H., and Weihe, E. (1995) Reserpine- and tetrabenazine- sensitive transport of 3H-histamine by the neuronal isoform of the vesicular monoamine transporter. J. Mol. Neurosci. 6: 277-287.
- Weihe, E., Schäfer, M.K.-H., Erickson, J.D., and Eiden, L.E. (1994) Localization of vesicular monoamine transporter isoforms (VMAT1 and VMAT2) to endocrine cells and neurons in rat. J. Mol. Neurosci. 5: 149-164.
- Schäfer, M.K.-H., Weihe, E., Erickson, J.D., and Eiden, L.E. (1995) Human and monkey cholinergic neurons visualized in paraffin-embedded tissues by immunoreactivity for VAChT, the vesicular acetylcholine transporter. J. Mol. Neurosci. 6: 225-235.
- Schäfer, M.K.-H., Weihe, E., Varoqui, H., Eiden, L.E., and Erickson, J.D. (1994) Distribution of the vesicular acetylcholine transporter (VAChT) in the central and peripheral nervous systems of the rat. J. Mol. Neurosci. 5: 1-26.
Erickson, J.D., Varoqui, H., Schäfer, M. K.-H., Modi, W., Diebler, M.-F., Weihe, E., Rand, J. B., Eiden, L.E., Bonner, T.I., and Usdin, T.B. (1994) Functional identification of a vesicular acetylcholine transporter and its expression from a 'cholinergic' gene locus. J. Biol. Chem. 269:21929-21932.
- Varoqui, H., Diebler, M.-F., Meunier, F.-M., Rand, J.B., Usdin, T.B., Bonner, T.I., Eiden, L.E., and Erickson, J.D. (1994) Cloning and expression of the vesamicol binding protein from the marine ray Torpedo: homology with the putative vesicular acetylcholine transporter UNC-17 from Caenorhabditis elegans. FEBS Lett. 342:97-102.
Erickson, J.D. and Eiden, L.E. (1993) Functional identification and molecular cloning of a human brain vesicle monoamine transporter.J. Neurochem. 61:2314-2317.
Erickson, J.D., Eiden, L.E., and Hoffman, B.J. (1992) Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc. Natl. Acad. Sci. 89:10993-10997.
Erickson, J.D., Masserano, J.M., Zoeller, R.T., and Weiner, N. (1991) Differential responsiveness of the pituitary-thyroid axis to thyrotropin-releasing hormone in mouse lines selected to differ in central nervous system sensitivity to ethanol. Endocrinology 128:3013-3020.
- Erickson, J.D., Masserano, J.M., Barnes, E., Ruth, J.A., and Weiner, N. (1990) Chloride ion increases 3H-dopamine accumulation by synaptic vesicles purified from rat striatum: inhibition by thiocyanate ion. Brain Res. 516:155-160.