Chris McBain, PhD, Chief
The Laboratory of Cellular and Synaptic Neurophysiology (LCSN) uses the techniques of neurophysiology, molecular biology, and cell biology to investigate signaling mechanisms related to the development, physiology, and pathophysiology of the mammalian central nervous system. LCSN researchers study receptors, ion channels, and signaling mechanisms in preparations that range from isolated cells to highly ordered neural networks in both physiological and pathophysiological conditions from both wild-type and transgenic animals. Problems under analysis concern mechanisms of short- and long-term plasticity of synaptic transmission, neurotrophin regulation of excitability and development, differential targeting of synaptic receptors and voltage-gated ion channels, pathophysiological processes in clinically relevant neuronal migration disorders, ion channel regulation of development and excitability, drug action at a variety of voltage- and ligand-gated receptors, and synaptic and network mechanisms that underlie sensory processing and memory formation, including coding mechanisms involving the oscillatory interactions of ensembles of interneurons in the insect antennal lobe.
Chris McBain's group, the Section on Cellular and Synaptic Physiology, has extensively characterized the role of the metabotropic glutamate receptor mGluR7 in controlling bi-directional synaptic plasticity at Ca-permeable, GluR2-lacking AMPA-receptors at synapses between dentate gyrus mossy fiber axons and CA3 stratum lucidum inhibitory interneurons. The researchers elucidated the role of muscarinic receptors in controlling interneuron excitability and their control over rhythmic and oscillatory activity within the hippocampal formation. They also investigated the role of voltage-gated potassium conductance (the M-current) in controlling spike timing in identified interneurons; they elucidated the mechanism for a use-dependent switch in polarity of inhibitory transmission between interneurons during high-frequency synaptic transmission and the switch's impact on the CA3 hippocampal network; the roles of specific kainate receptor subunits in kainate-induced hippocampal gamma oscillatory activity; and the roles of PICK1 in novel mechanisms of long-lasting depression of synaptic transmission at mossy fiber–A3 pyramidal neuron synapses.
Bai Lu and his colleagues in the Section on Neuronal Development demonstrated that brain-derived neurotrophic factor (BDNF) induces a rapid translocation of its receptor TrkB into lipid rafts, which are micromembrane domains enriched at synapses; discovered cAMP gating of TrkB signaling and its role in dendritic spine formation in the hippocampus; determined that proBDNF, through activation of the p75 neurotrophin receptor (p75NTR), facilitates hippocampal long-term depression (LTD), an effect mediated by proBDNF regulation of NR2B, a specific subtype of NMDA receptor critical for LTD; and proposed a yin-yang model in which pro- and mature neurotrophins elicit diametrically opposing effects through activation of two distinct receptors: p75NTR and Trk receptor tyrosine kinases.
Dax Hoffman’s group, the Molecular Neurophysiology and Biophysics Unit, demonstrated a role for Kv4.2 in regulating dendritic AP propagation by using Ca2+ imaging. Specifically, the researchers demonstrated no change in the voltage dependence of activation or inactivation with Kv4.2 overexpression or Kv4.2 dominant negative expression in hippocampal organotypic slice cultures, supporting the assertion that the molecular identity of the native A-type channel is Kv4.2. Hoffman’s group also found spine enrichment of EGFP-tagged Kv4.2 in cultured hippocampal neurons, elucidated the role of Kv4.2 in frequency-dependent action potential broadening in hippocampal pyramidal neurons, and showed an NMDA- and Ca-dependent redistribution of Kv4.2 out of the membrane induced by a variety of stimulus paradigms, including a redistribution of Kv4.2 out of spines with a chemically induced form of long-lasting potentiation (cLTP). Finally, the Unit found that cLTP is not induced in cultured neurons overexpressing Kv4.2 and observed that, while LTP in organotypic slice cultures is not maintained in Kv4.2-overexpressing neurons, it is not significantly altered by dominant negative Kv4.2 expression.
Mark Stopfer and his colleagues in the Unit on Sensory Coding quantified several forms of short- and long-term peripheral and central neural plasticity in the olfactory system, demonstrated that a distributed spatio-temporal neural code can efficiently form an invariant representation of a complex, temporally structured sensory stimulus, and demonstrated that ensembles of moth olfactory neurons show information-rich, oscillatory synchronization when the animal is exposed to odorant. In addition, the Unit developed techniques to make intracellular recordings from specific genetically tagged neurons in the Drosophila olfactory system, thus preparing for a mechanistic analysis of olfactory coding; found that olfactory interneurons also respond to temperature shifts; and began an analysis of multimodal sensory processing. Finally, the Unit demonstrated that naive, newly born locusts display specific, food-related odor preferences, and researchers began analysis of neural coding of innate information.