Affiliations

Professor, Neurology, Physiology

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.

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