Chris McBain, PhD, Chief

The Laboratory of Cellular and Synaptic Neurophysiology (LCSN) uses neurophysiology, molecular biology, and cell biology to study 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 numerous 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 underlying 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 Cellular and Synaptic Physiology Section, characterized the role of mGluR7, the metabotropic glutamate receptor, in controlling bi-directional synaptic plasticity at calcium-permeable, GluR2-lacking, AMPA receptors at synapses between dentate gyrus mossy fiber axons and CA3 stratum lucidum inhibitory interneurons. The group also demonstrated that persistent depression of presynaptic mossy fiber filopodial voltage-gated calcium channels underlies this long-term depression (LTD). In addition, the laboratory described a novel form of depolarization-induced LTD at mossy fiber-CA3 pyramidal cell synapses linked to the developmental, transient expression of calcium-permeable AMPA receptors. The researchers investigated the role of the M-current, the voltage-gated potassium conductance, in controlling spike timing in identified interneurons and identified a role for the pH-sensitive TASK-like conductance in a specific subpopulation of interneurons.

Dax Hoffman's group, the Molecular Neurophysiology and Biophysics Unit, demonstrated that activity-dependent redistribution of the voltage-gated K+ subunit Kv4.2 is mediated through clathrin-dependent endocytosis. The researchers found that the Kv4.2 expression level affects synaptic current size and that stimulating Kv4.2 internalization enhances synaptic currents. Moreover, they found evidence for Kv4.2 internalization during chemically and synaptically induced long-term potentiation. Live-imaging studies demonstrated that Kv4.2 internalization occurs rapidly upon stimulation but then progresses over the course of 15 to 20 minutes. Biotinylation assays showed that nearly all Kv4.2 returns to the cell surface within four hours. In siRNA knockdown studies targeting the Kv4.2 auxiliary subunit DPPX, the laboratory showed that the membrane protein is a critical determinant of hippocampal CA1 pyramidal neuron membrane and firing properties, including input resistance, action potential onset, action potential threshold, action potential half-width, and action potential firing frequency. Thus, siDPPX had contrasting effects, decreasing the excitability subthreshold and increasing the excitability suprathreshold. Both effects are potentially explained by the shift in inactivation and activation curves, respectively.

Bai Lu and his colleagues in the Section on Neuronal Development studied mechanisms underlying long-term synaptic modulation induced by neurotrophin-3 (NT-3). They identified three characteristic features required for long-term, but not acute, forms of synaptic modulation by NT-3: endocytosis of neurotrophin-receptor complex, activation of Akt, and new protein synthesis. They further showed that NT-3 utilizes two parallel but distinct molecular pathways (CaMKIV-CREB and Rap1-MAPK) to elicit long-term changes in, respectively, synaptic function and structure. In addition, the group provided evidence for a link between adult neurogenesis, dentate LTP, and learning and memory. The researchers showed that FGF-R1-mediated proliferation of neuronal progenitor cells (NPCs) is important for memory consolidation, whereas NT-3-mediated NPC differentiation is involved in spatial learning.

Mark Stopfer and his group, the Unit on Sensory Coding and Neural Ensembles, examined how a well-characterized neural circuit extracts invariant information about the environment; they found that first-order interneurons confound the temporal patterns of odor plumes with the temporal structure of the neural representation but that follower interneurons can resolve the confounding effects by integrating many inputs over short periods of time. Combining physiology and computational modeling techniques, they also revealed how synaptic plasticity within the antennal lobe leads to reliable and noise-resistant odor encoding. They found that two forms of activity-dependent plasticity, one peripheral and one central, interact in complex ways to reshape the coding of odor plumes, providing gain control and timing-sensitive gating. Last, they found that moths use an oscillatory synchronization mechanism to encode odors and a very sparse coding scheme to represent odors in the mushroom bodies and that activity in the mushroom bodies correlates with behavioral responses. These results will enable a combined behavioral and physiological analysis of the neural basis of perception and memory.