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Program in Developmental Neuroscience

Director: Chris J. McBain, PhD

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The Program on Developmental Neuroscience (PDN) takes a comprehensive approach to the study of developmental neuroscience by using techniques of neurophysiology, molecular and cellular biology, crystallography, and imaging. Overall, the research focuses on the development, physiology, and pathophysiology of the mammalian central nervous system. Researchers study receptors, ion channels, and cellular and synaptic signaling mechanisms in preparations that range from isolated proteins and cells to highly ordered neural networks in both physiological and pathophysiological conditions observed in both wild-type and numerous transgenic animals.

Tamás Balla's Section on Molecular Signal Transduction investigates the role of phosphoinositide-derived messengers in mediating the actions of hormones, growth factors, and neurotransmitters in mammalian cells. The Section's studies focus on the cellular functions of phosphatidylinositol 4-kinase (PI4K) enzymes that regulate the first committed step in phosphoinositide synthesis. Over the last year, the Section developed a new method to rapidly eliminate PtdIns4P selectively from Golgi membranes and showed that exit of various cargos from the Golgi was blocked once PtdIns4P was removed. In collaborative studies, the contact zones between the mitochondria and the endoplasmic reticulum and the local Ca2+ concentration in these microdomains were visualized for the first time. The Section was also involved in studies that showed PI4K type-IIIbeta to be critical for the replication of small RNA viruses such as polio and cocxsackievirus, which opens new possibilities to fight these viral infections.

Andres Buonanno, who heads the Section on Molecular Neurobiology, and his colleagues the focus on the Neuregulin (NRG)–ErbB signaling pathway. Importantly, genes encoding the neurotrophic factors NRG-1 and NRG-3, as well as their receptor ErbB4, were identified as "at risk" genes for schizophrenia and other psychiatric disorders. Using a combination of molecular, cellular, electrophysiological, and behavioral approaches, the SMN found that NRG-1 reverses long-term potentiation at glutamatergic synapses via a novel signaling pathway linking activation of ErbB4 to dopamine release and that downstream activation of D4 dopamine receptors triggers the rapid internalization of surface glutamate receptors. In collaborative studies, the SMN also showed that NRG-1 signaling modulates gamma oscillatory network activity, and that this activity requires ErbB4 receptors expressed in fast-spiking interneurons. The functional link between NRG-1/ErbB4 signaling with glutamatergic transmission and D4 dopamine receptors (a target for clozapine and other antipsychotics), and its link through GABAergic neurons to modulate gamma oscillation power (reduced in schizophrenia patients), begins to uncover pathways that are genetically, pharmacologically, and functionally implicated in cognitive functions and psychiatric disorders.

Dax Hoffman's Unit on Molecular Neurophysiology and Biophysics continues to investigate the role of the voltage-gated K+ channel subunits in the regulation of dendritic excitability and synaptic integration of hippocampal neurons. Over the past year, the Unit discovered that distance-dependent dendritic Kv4.2 mobility is regulated by activity-dependent phosphorylation of Kv4.2 by protein kinase A (PKA). The source of PKA modulation was identified as a novel accessory subunit for Kv4.2A, AKAP79/150, which provides a platform for dynamic PKA regulation of Kv4.2 expression, critically impacting neuronal excitability. Studies in heterologous expression systems showed that Kv4 a-subunits interact with an additional auxiliary subunit, DPP6, which was recently identified in large copy-number variants screens as an Autism Spectrum Disorder and ALS target gene. In dendritic recordings from DPP6 knockout mice, the lab discovered that DPP6 is critical for generating the A-type K+ current gradient observed in CA1 dendrites. The loss this gradient led to hyper-excitable dendrites, with implications for information storage and coding.

Kuo-Ping Huang's Section on Metabolic Regulation investigates the signaling mechanisms involved in synaptic plasticity. Using neurogranin (Ng) knockout mice, the Section demonstrated the protein's critical role in the expression of LTP and normal cognitive function. Environmental enrichment and treatment with Ritalin® ameliorated the behavioral impairments of young adult Ng-knockout mice.

Y. Peng Loh's Section on Cellular Neurobiology explores the mechanisms of intracellular trafficking and secretion of peptide hormones, neuropeptides, and neurotrophins in endocrine cells and neurons, as well as the role of the prohormone processing enzyme carboxypeptidase E in stress, neuroprotection, and tumorogenesis. Major accomplishments over the past year include: establishing the role of serpinin, a novel secreted chromogranin A–derived peptide, in regulating dense core secretory granule biogenesis through a cAMP-PKA-sp1 pathway, in an autocrine manner, in pituitary corticotrophic cells; and elucidation of the mechanism of action of a novel splice isoform of carboxypeptidase E in promoting tumor metastasis, as well as clinical studies demonstrating that the enzyme is a powerful prognostic biomarker for predicting future metastasis in hepatocellular carcinoma and pheochromocytoma patients.

Mark Mayer's Section on Neurophysiology and Biophysics investigates ionotropic glutamate receptors (iGluRs)—the molecular pores that mediate signal transmission at the majority of excitatory synapses in the mammalian central nervous system. Given the receptors' essential role in normal brain function and development and increasing evidence that dysfunction of GluR activity mediates several central nervous system diseases and damage during stroke, the Section studies receptor mechanisms by combining atomic-resolution structural data obtained by X-ray diffraction and functional data collected from rapid perfusion techniques and patch clamp recording.

Chris McBain's Section on Cellular and Synaptic Physiology investigates the development and regulation of cortical excitability, in particular glutamatergic and GABAergic synaptic transmission and plasticity in the hippocampal formation. Mechanisms underlying the differential regulation of transmitter release at functionally divergent presynaptic terminals along a common axon, the roles of ionotropic and metabotropic glutamatergic and cholinergic receptors in controlling cell excitability, and bidirectional synaptic plasticity at both inhibitory and excitatory axon terminals are emphasized.

Stanko Stojilkovic, who heads the Section on Cellular Signaling, and colleagues investigate signaling pathways in pituitary cells. The Section characterized the role of multidrug-resistance proteins 4 and 5 in cyclic nucleotide efflux and the dependence of these transporters on membrane potential in cultured pituitary cells. In related studies, the role of calmodulin kinase II in stimulus-secretion coupling was addressed as well as the role of prostaglandins in autoregulation of GnRH receptors. The Section also characterized molecular, pharmacological, and functional properties of P2X4 receptor channels in normal and immortalized pituitary cells and their roles in electrical activity, calcium signaling, and secretion. The Section's also showed that heavy metals and reactive oxygen species are allosteric modulators of P2X2 receptor channels cloned from the pituitary gland.

Mark Stopfer's group, the Unit on Sensory Coding and Neural Ensembles, is interested in understanding how brain mechanisms gather and organize sensory information to build transient and sometimes enduring internal representations of an animal's surroundings; the animal actively collects information, which is then processed and dramatically transformed in myriad ways. The Unit's goal is to understand the fundamental mechanisms by which sensory information is collected, transformed, stabilized, and compared as it makes its way through the nervous system. Using relatively simple animals and focusing primarily on olfaction, the Unit combines electrophysiological, anatomical, genetic, behavioral, computational, and other strategies to examine how fully intact neural circuits, driven by real sensory stimuli, process information.

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