Professor, Neurology, University of California Los Angeles
Professor, Physiology, University of California Los Angeles
635 Charles Young Dr S
Los Angeles, CA 90095 635 Charles Young Dr S
Los Angeles, CA 90095
Office Phone Number:
Member, Brain Research Institute, Molecular Pharmacology GPB Home Area, Molecular, Cellular & Integrative Physiology GPB Home Area, Neuroengineering Training Program, Neuroscience GPB Home Area
My research focuses on the physiology and pharmacology of synaptic transmission in the mammalian brain, and the regulation of intracellular calcium homeostasis. These two themes ultimately converge in the lab. Our principal interest is finding out how they both relate to long-term alterations in the excitability of nerve cells and circuits that are responsible for offsetting the frail balance between excitation and inhibition. When this balance is tipped, either acutely of chronically, the nervous system shows signs of aberrant activity leading to specific brain disorders. The experimental approaches we use include patch-clamp recordings (whole-cell, single channel and perforated patch) in brain slices, in acutely isolated animal and human neurons, or in cultured neurons, or in cultured neurons/slices; chronic recordings in vivo to monitor long-term changes in the excitability of circuits; infrared and fluorescent video microscopy and simultaneous recordings in live brain tissue; various neuroanatomical and immunohistochemical techniques; measurement of intraneuronal calcium; molecular biological approaches aimed at reducing specific brain proteins by using antisense oligonucleotides and genetic knockouts. Synaptic transmission in being studied by recording synaptic currents resulting from the brief activation of various ligand-gated receptor/channels by excitatory (e.g., L-glutamate) or inhibitory (e.g., g -aminobutyric acid or GABA) amino acid neurotransmitters in grain slices. Novel electrophysiological methods allow us to establish the conductance, number, kinetics and modulation by second messengers of the postsynaptic receptor/channels and the presynaptic processes that control neurotransmitter release. Molecular biological and pharmacological approaches are aimed at disabling certain receptor types while conserving others, to investigate the relative contribution of specific receptors to synaptic transmission, and to reveal the fundamental mechanisms underlying receptor subunit assembly and aggregation at synapses. The contribution of neuron-specific intracellular calcium-binding proteins to the overall calcium homeostasis is being explored through recording calcium-dependent physiological events and calcium imaging in neurons. We are presently focusing on two proteins: calbindin-D28K and parvalbumin; both are conspicuously localized only in certain cell types, and can change the physiological response of nerve cells to calcium loading. Elevations of intracellular calcium, and omnipotent second messenger, man initiate neuronal events ranging form cellular memory to neuronal death. We are gaining insight into how cellular functions are being controlled by these proteins by using genetic knockout mice and by examining pathological conditions that alter their cellular content. Current projects involve the physiological basis of synaptic transmission and pathological changes that take place during epilepsy, brain trauma/hypoxia, or Alzheimer’s disease. For example, we are presently studying the cellular and molecular mechanisms responsible for the long-term changes in the function of ligand-gated channels (NMDA) and calcium homeostasis in neurons form chronically epileptic animals and in human nerve cells obtained from surgically removed temporal lobe specimens. We are just beginning to unveil how an altered state of neuronal excitability can be sustained for a long time.
Synaptic Signaling in Health and Disease Our research focuses on 1) the physiology, pharmacology, and pathology of synaptic transmission in the mammalian brain, and 2) the regulation of intracellular calcium homeostasis. The two themes ultimately converge in our quest for understanding how long-term alterations in the excitability of nerve cells and circuits are responsible for offsetting the frail balance between excitation and inhibition. Tipping this balance, either acutely of chronically, results in the nervous system showing signs of abnormal activity leading to specific brain disorders. We study synaptic transmission and the activation of extrasynaptic receptors in the healthy and the diseased brain. We presently carry out research in animal models of epilepsy, Huntington’s disease, stress, alcoholism, PMS/PMDD, postpartum depression, while also recording from human brain tissue surgically removed for the treatment of epilepsies. By studying the fundamental mechanisms responsible for the altered synapses and circuits our studies will lead to novel therapies for a number of devastating neurological and psychiatric disorders. The experimental approaches we use include patch-clamp recordings (whole-cell, single channel and perforated patch) in brain slices, in acutely isolated animal and human neurons, or in cultured neurons/slices; chronic recordings in vivo to monitor long-term changes in the excitability of circuits; infrared and fluorescent video microscopy and simultaneous recordings in live brain tissue; various neuroanatomical and immunohistochemical techniques; measurement of intraneuronal calcium and the binding kinetics of calcium to various calcium-binding proteins; molecular biological approaches aimed at reducing or altering specific brain proteins as in genetic knockouts/knockins and various methods aimed at altering cellular protein levels.
A selected list of publications:
- Engel Jerome, Thompson Paul M, Stern John M, Staba Richard J, Bragin Anatol, Mody Istvan Connectomics and epilepsy Current opinion in neurology, 2013; 26(2): 186-94.
- Engel Jerome, PitkÃ¤nen Asla, Loeb Jeffrey A, Edward Dudek F, Bertram Edward H, Cole Andrew J, MoshÃ© Solomon L, Wiebe Samuel, Jensen Frances E, Mody Istvan, Nehlig Astrid, Vezzani Annamaria Epilepsy biomarkers Epilepsia, 2013; 54 Suppl 4: 61-9.
- Ferando Isabella, Mody Istvan GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies Epilepsia, 2012; 53 Suppl 9(2): 89-101.
- Faas Guido C, Mody Istvan Measuring the kinetics of calcium binding proteins with flash photolysis Biochimica et biophysica acta, 2012; 1820(8): 1195-204.
- Faas Guido C, Raghavachari Sridhar, Lisman John E, Mody Istvan Calmodulin as a direct detector of Ca2+ signals Nature neuroscience, 2011; 14(3): 301-4.
- Barth Albert M I, Mody Istvan Changes in hippocampal neuronal activity during and after unilateral selective hippocampal ischemia in vivo The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011; 31(3): 851-60.
- Tao Jifang, Wu Hao, Lin Quan, Wei Weizheng, Lu Xiao-Hong, Cantle Jeffrey P, Ao Yan, Olsen Richard W, Yang X William, Mody Istvan, Sofroniew Michael V, Sun Yi E Deletion of astroglial Dicer causes non-cell-autonomous neuronal dysfunction and degeneration The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011; 31(22): 8306-19.
- Mody Istvan, Maguire Jamie The reciprocal regulation of stress hormones and GABA(A) receptors Frontiers in cellular neuroscience, 2011; 6(3): 4.
- Gehman Lauren T, Stoilov Peter, Maguire Jamie, Damianov Andrey, Lin Chia-Ho, Shiue Lily, Ares Manuel, Mody Istvan, Black Douglas L The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain Nature genetics, 2011; 43(7): 706-11.
- Mann Edward O, Mody Istvan Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons Nature neuroscience, 2010; 13(2): 205-12.
- Clarkson Andrew N, Huang Ben S, Macisaac Sarah E, Mody Istvan, Carmichael S Thomas Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke Nature, 2010; 468(7321): 305-9.
- Wyeth Megan S, Zhang Nianhui, Mody Istvan, Houser Carolyn R Selective reduction of cholecystokinin-positive basket cell innervation in a model of temporal lobe epilepsy The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010; 30(26): 8993-9006.
- Maguire Jamie, Ferando Isabella, Simonsen Charlotte, Mody Istvan Excitability changes related to GABAA receptor plasticity during pregnancy The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009; 29(30): 9592-601.
- Engel Jerome, Bragin Anatol, Staba Richard, Mody Istvan High-frequency oscillations: what is normal and what is not? Epilepsia, 2009; 50(4): 598-604.
- Elsas Siegward-M, Hazany Saman, Gregory William L, Mody Istvan Hippocampal zinc infusion delays the development of afterdischarges and seizures in a kindling model of epilepsy Epilepsia, 2009; 50(4): 870-9.
- Maguire Jamie, Mody Istvan Steroid hormone fluctuations and GABA(A)R plasticity Psychoneuroendocrinology, 2009; 34 Suppl 1(2): S84-90.
- Mody Istvan “One swallow does not make a summer” … or does it? Epilepsy currents / American Epilepsy Society, 2008; 8(3): 73-5.
- Mody Istvan Extrasynaptic GABAA receptors in the crosshairs of hormones and ethanol Neurochemistry international, 2008; 52(1-2): 60-4.
- Maguire Jamie, Mody Istvan GABA(A)R plasticity during pregnancy: relevance to postpartum depression Neuron, 2008; 59(2): 207-13.
- Cui Yijun, Costa Rui M, Murphy Geoffrey G, Elgersma Ype, Zhu Yuan, Gutmann David H, Parada Luis F, Mody Istvan, Silva Alcino J Neurofibromin regulation of ERK signaling modulates GABA release and learning Cell, 2008; 135(3): 549-60.
- Sokolova Irina V, Mody Istvan Silencing-induced metaplasticity in hippocampal cultured neurons Journal of neurophysiology, 2008; 100(2): 690-7.
- Mann Edward O, Mody Istvan The multifaceted role of inhibition in epilepsy: seizure-genesis through excessive GABAergic inhibition in autosomal dominant nocturnal frontal lobe epilepsy Current opinion in neurology, 2008; 21(2): 155-60.
- Glykys Joseph, Mann Edward O, Mody Istvan Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus? The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008; 28(6): 1421-6.
- Mody Istvan, Glykys Joseph, Wei Weizheng A new meaning for “Gin & Tonic”: tonic inhibition as the target for ethanol action in the brain Alcohol (Fayetteville, N.Y.), 2007; 41(3): 145-53.
- Glykys Joseph, Peng Zechun, Chandra Dev, Homanics Gregg E, Houser Carolyn R, Mody Istvan A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol Nature neuroscience, 2007; 10(1): 40-8.
- Glykys Joseph, Mody Istvan Activation of GABAA receptors: views from outside the synaptic cleft Neuron, 2007; 56(5): 763-70.
- Zhang Nianhui, Wei Weizheng, Mody Istvan, Houser Carolyn R Altered localization of GABA(A) receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007; 27(28): 7520-31.
- Farshchi Shahin, Pesterev Aleksey, Nuyujukian Paul H, Mody Istvan, Judy Jack W Bi-Fi: an embedded sensor/system architecture for REMOTE biological monitoring IEEE transactions on information technology in biomedicine : a publication of the IEEE Engineering in Medicine and Biology Society, 2007; 11(6): 611-8.
- Maguire Jamie, Mody Istvan Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007; 27(9): 2155-62.
- Faas Guido C, Schwaller Beat, Vergara Julio L, Mody Istvan Resolving the fast kinetics of cooperative binding: Ca2+ buffering by calretinin PLoS biology, 2007; 5(11): e311.
- Spampanato Jay, Mody Istvan Spike timing of lacunosom-moleculare targeting interneurons and CA3 pyramidal cells during high-frequency network oscillations in vitro Journal of neurophysiology, 2007; 98(1): 96-104.
- Glykys, J. and Mody, I. The activation of GABAA receptors: the view from outside the synaptic cleft, Neuron, 2007; 56: 763-770.
- Glykys Joseph, Mody Istvan The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus The Journal of physiology, 2007; 582(Pt 3): 1163-78.
- Farshchi Shahin, Nuyujukian Paul H, Pesterev Aleksey, Mody Istvan, Judy Jack W A TinyOS-enabled MICA2-based wireless neural interface IEEE transactions on bio-medical engineering, 2006; 53(7): 1416-24.
- Glykys Joseph, Mody Istvan Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-deficient mice Journal of neurophysiology, 2006; 95(5): 2796-807.
- Klaassen Alwin, Glykys Joseph, Maguire Jamie, Labarca Cesar, Mody Istvan, Boulter Jim Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy Proceedings of the National Academy of Sciences of the United States of America, 2006; 103(50): 19152-7.
- Chanda Baron, Blunck Rikard, Faria Leonardo C, Schweizer Felix E, Mody Istvan, Bezanilla Francisco A hybrid approach to measuring electrical activity in genetically specified neurons Nature neuroscience, 2005; 8(11): 1619-26.
- Mody Istvan Another “tonic” in the realm of epilepsy Epilepsy currents / American Epilepsy Society, 2005; 4(6): 248-9.
- Mody Istvan Aspects of the homeostaic plasticity of GABAA receptor-mediated inhibition The Journal of physiology, 2005; 562(Pt 1): 37-46.
- Chiu Chi-Sung, Brickley Stephen, Jensen Kimmo, Southwell Amber, Mckinney Sheri, Cull-Candy Stuart, Mody Istvan, Lester Henry A GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005; 25(12): 3234-45.
- Faas Guido C, Karacs Kinga, Vergara Julio L, Mody Istvan Kinetic properties of DM-nitrophen binding to calcium and magnesium Biophysical journal, 2005; 88(6): 4421-33.
- Maguire Jamie L, Stell Brandon M, Rafizadeh Mahsan, Mody Istvan Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety Nature neuroscience, 2005; 8(6): 797-804.
- Gu Xiaofeng, Li Chenjian, Wei Weizheng, Lo Victor, Gong Shiaoching, Li Shi-Hua, Iwasato Takuji, Itohara Shigeyoshi, Li Xiao-Jiang, Mody Istvan, Heintz Nathaniel, Yang X William Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice Neuron, 2005; 46(3): 433-44.
- Farshchi Shahin, Mody Istvan, Judy Jack W A TinyOS-based wireless neural interface Conference proceedings : … Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference, 2004; 6(9): 4334-7.
- Peng Zechun, Huang Christine S, Stell Brandon M, Mody Istvan, Houser Carolyn R Altered expression of the delta subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004; 24(39): 8629-39.
- Mody Istvan, Pearce Robert A Diversity of inhibitory neurotransmission through GABA(A) receptors Trends in neurosciences, 2004; 27(9): 569-75.
- Bragin Anatol, Wilson Charles L, Almajano Joyel, Mody Istvan, Engel Jerome High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis Epilepsia, 2004; 45(9): 1017-23.
- Mody, I. and Pearce, R.A. Interneuron diversity series: Diversity of inhibitory neurotransmission through GABAA receptors, Trends in Neurosci, 2004; 27: 569-575.
- Wei Weizheng, Faria Leonardo Coutinho, Mody Istvan Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004; 24(38): 8379-82.
- Stell Brandon, Mody Istvan A tale of timing and transport Neuron, 2003; 39(5): 729-30.
- Dalby Nils Ole, Mody Istvan Activation of NMDA receptors in rat dentate gyrus granule cells by spontaneous and evoked transmitter release Journal of neurophysiology, 2003; 90(2): 786-97.
- Mody Istvan Calcium and Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) Epilepsy currents / American Epilepsy Society, 2003; 3(6): 221-222.
- Jensen Kimmo, Chiu Chi-Sung, Sokolova Irina, Lester Henry A, Mody Istvan GABA transporter-1 (GAT1)-deficient mice: differential tonic activation of GABAA versus GABAB receptors in the hippocampus Journal of neurophysiology, 2003; 90(4): 2690-701.
- Ren Xiuhai, Mody Istvan Gamma-hydroxybutyrate reduces mitogen-activated protein kinase phosphorylation via GABA B receptor activation in mouse frontal cortex and hippocampus The Journal of biological chemistry, 2003; 278(43): 42006-11.
- Stell Brandon M, Brickley Stephen G, Tang C Y, Farrant Mark, Mody Istvan Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors Proceedings of the National Academy of Sciences of the United States of America, 2003; 100(24): 14439-44.
- Wei Weizheng, Zhang Nianhui, Peng Zechun, Houser Carolyn R, Mody Istvan Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003; 23(33): 10650-61.
- Behr Joachim, Gebhardt Christine, Heinemann Uwe, Mody Istvan Kindling enhances kainate receptor-mediated depression of GABAergic inhibition in rat granule cells The European journal of neuroscience, 2002; 16(5): 861-7.
- Bragin Anatol, Mody Istvan, Wilson Charles L, Engel Jerome Local generation of fast ripples in epileptic brain The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002; 22(5): 2012-21.
- Chiu Chi-Sung, Jensen Kimmo, Sokolova Irina, Wang Dan, Li Ming, Deshpande Purnima, Davidson Norman, Mody Istvan, Quick Michael W, Quake Stephen R, Lester Henry A Number, density, and surface/cytoplasmic distribution of GABA transporters at presynaptic structures of knock-in mice carrying GABA transporter subtype 1-green fluorescent protein fusions The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002; 22(23): 10251-66.
- Stell Brandon M, Mody Istvan Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002; 22(10): RC223.
- Nusser Zoltan, Mody Istvan Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells Journal of neurophysiology, 2002; 87(5): 2624-8.
- Mody Istvan The GAD-given Right of Dentate Gyrus Granule Cells to Become GABAergic Epilepsy currents / American Epilepsy Society, 2002; 2(5): 143-145.