Istvan Mody

Istvan Mody

Professor, Neurology, University of California Los Angeles

Professor, Physiology, University of California Los Angeles

(310) 206-3484

635 Charles Young Dr S
Los Angeles, CA 90095 635 Charles Young Dr S
Los Angeles, CA 90095

Office Phone Number:
310-206-4481

Affiliations

Member, Brain Research InstituteMolecular Pharmacology GPB Home AreaMolecular, Cellular & Integrative Physiology GPB Home AreaNeuroengineering Training ProgramNeuroscience GPB Home Area

Research Interests

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.

Biography

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.

Publications

A selected list of publications: