Gill Seminars
Previous Speakers
November 13, 2009
Edwin Rubel, Ph.D.
University of Washington
Seminar will be held in Woodburn Hall, Room 120 at 1:30 p.m.
Title: "Experience and Auditory Brainstem Development: Signals, Cellular Events and Critical Periods"
Abstract: Since the classic experiments of Hamburger, Levi-Montalcini, and Hubel & Wiesel, a large variety of studies have shown that manipulations of peripheral input and sensory experience can have profound influences on the development of sensory encoding pathways of the central nervous
system. Yet, relatively little is known about the cellular mechanisms whereby changes in sensory system function influence the structure or integrity of CNS elements. We have used the brainstem auditory pathways of birds and mammals to investigate the early cellular events underlying
deprivation- and deafferentation-induced changes in the structure and integrity of neurons and glial cells. Our work in this area uses a variety of methodologies on /in vivo/ and /in vitro /preparations of the brainstem to address three issues related to activity-regulated development and maintenance of auditory brainstem neurons. What is the nature of the _inter_cellular signals regulating structural integrity of postsynaptic neurons? What are some of the _intra_cellular cascades of events underlying deprivation-induced changes in neuronal integrity? What biological mechanisms may underlie developmental differences in responses to peripheral manipulations (critical periods)?
I will briefly summarize our approach to these problems and then discuss two lines of recent and ongoing experiments. First, using normal and transgenic mice, and microarray technology we have focused understanding the differential susceptibility of neonatal and adult sensory systems to
neuronal death due to deprivation of afferent activity (a critical period). I will present results indicating that downstream regulators of cell death can dramatically modulate the critical period response and
that the switch from deprivation sensitive to deprivation insensitive probably involves the orchestrated changes transcription of many cell death regulatory genes. These experiments emphasize the developmental transition from selection pressures to optimize plasticity of the growing nervous system to selection pressures emphasizing stability. Second, I will present results of a series of experiments that address the dynamic changes seen in individual dendritic arbors as a function of
the integrity and activity of excitatory synaptic input. The symmetrical, segregated input to the dendrites of nucleus laminaris provide a unique model to investigate dynamic changes in dendritic
structure and intracellular events that may underlie local modifications of dendritic structure.
Support provided by NIDCD.
________________________________________________________________
October 28, 2009
Loren H. Parsons, Ph.D.
The Scripps Research Institute
Seminar will be held in Psychological and Brain Sciences, Room PY101 at 4:00 p.m.
Title: "An evaluation of brain endocannabinoid signaling and addiction-related behaviors"
Abstract:Addictive drugs exert their behavioral and reinforcing effects through actions on multiple neurotransmitter systems including monoamines, endogenous opioids, and both excitatory and inhibitory amino acids. A growing body of literature also points to an involvement of the endogenous cannabinoid system in the etiology of drug addiction. For example there is evidence of a significant correlation between allelic variances in the cannabinoid-1 (CB1) receptor gene and the incidence of drug dependence in humans. Similarly, a naturally occurring single nucleotide polymorphism in the gene encoding the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) is associated with problem drug and alcohol use. A substantial amount of preclinical data also points to a CB1 receptor influence in regulating the self-administration of alcohol, opiates and nicotine. However, little is known of the mechanisms through which endocannabinoids modulate drug-induced behaviors and there is even less understanding of the effects of prolonged drug exposure on endocannabinoid signaling. This lecture will provide in vivo evidence that voluntary drug intake alters extracellular endocannabinoid levels in the rodent brain in a manner that modulates the motivation for continued drug intake. Data demonstrating altered endocannabinoid function following chronic drug exposure will also be presented along with evidence that this dysfunction contributes to excessive drug intake through negative reinforcement mechanisms.
[Hosts – Ken Mackie and Heather Bradshaw]
Sponsored by the Neuroscience Training Grant, and the Gill Center
_____________________________________________________________________
October 12, 2009
Erika Holzbaur, Ph.D.
University of Pennsylvania
School of Medicine
Seminar will be held in Jordan Hall, Room 009 at 4:00 p.m.
Title: "Motor Neurons Require Motor Proteins: Molecular Motors, Axonal Transport, and Neurodegeneration"
Research Description:Our laboratory is focused on the microtubule-based motor cytoplasmic dynein and its activator dynactin. Dynein and dynactin are required for vesicular trafficking, microtubule organization, mitotic spindle assembly, and development of polarity. We are interested in the mechanisms of force production and motor function, mechanisms of cargo coupling and regulation, effects of dynein and dynactin on dynamics of the cytoskeleton, and the analysis of neurodegenerative diseases resulting from impairments in dynein/dynactin function. Disruptions in dynein/dynactin function cause motor neuron degeneration and muscle atrophy, leading to motor neuron diseases similar to ALS. Approaches in the lab include in vitro motility assays for motors, microtubules and organelles, biochemical and cellular assays for binding partners, live cell microscopy, and development and characterization of transgenic mouse models for motor neuron disease.
______________________________________________________________________
May 20, 2009
Daniel Johnston, Ph.D.
University of Texas at Austin
2009 Gill Symposium, May 20, 2009, 3:30 p.m., Indiana Memorial Union, Whittenberger Auditorium
Title: Active dendrites are the colorful wings of the mysterious butterflies
Abstract:
Santiago Ramón y Cajal referred to neurons as the “mysterious butterflies of the soul”. The wings of these butterflies—their dendrites—were traditionally considered as passive integrators of synaptic information. It is now widely accepted that these wings are ‘colorful’, that is, they are endowed with a mosaic of voltage-gated ion channels, with each family of neurons, or ‘butterflies’ made of distinct hues and shades. Rapidly evolving evidence provides direct and indirect demonstrations for activity-dependent plasticity of these ion channels, pointing towards chameleonic adaptability in these hues. We have focused our efforts on two of these channels, a fast transient potassium channel and a hyperpolarization-activated cation (h) channel. Both are highly expressed in dendrites of hippocampal neurons and both play important roles in regulating the intrinsic excitability of these cells. The h-channel is particularly interesting because it shows bi-directional changes in function with long-term synaptic potentiation and depression and in certain disease states. This presentation will discuss the background of this field as well as recent work related to dendritic ion channel plasticity.
______________________________________________________________________
May 20, 2009
Linda Hsieh-Wilson, Ph.D.
California Institute of Technology
2009 Gill Symposium, May 20, 2009, 11:30 a.m., Indiana Memorial Union, Whittenberger Auditorium
Title: Uncovering roles for carbohydrates in axonal growth and regeneration
Abstract:
The field of chemical neurobiology is rapidly evolving and providing insights into the molecules and interactions involved in brain development, neuronal communication and memory storage. We will describe the synergistic application of organic chemistry and neurobiology to explore the structure and function of chondroitin sulfate glycosaminoglycans in the nervous system and their impact on neuronal growth and spinal cord regeneration.
______________________________________________________________________________
May 20, 2009
Rajesh Khanna, Ph.D.
Department of Pharmacology and Toxicology and the Paul and Carole Stark Neurosciences Research Institute and, Indiana University School of Medicine.
2009 Gill Symposium, May 20, 2009, 9:15 a.m., Indiana Memorial Union, Whittenberger Auditorium
Title: Regulation of neurite outgrowth and synaptic efficacy by calcium channel-CRMP-2 interactions
Abstract:
Collapsin response mediator proteins (CRMPs) specify axon/dendrite fate and axonal growth of neurons through protein-protein interactions. Their functions in presynaptic biology remain unknown. Here, we identify the presynaptic N-type Ca2+ channel (CaV2.2) as a CRMP-2–interacting protein. CRMP-2 binds directly to CaV2.2. Both proteins co-localize within presynaptic sites in hippocampal neurons. Overexpression into hippocampal neurons of a CRMP-2 protein fused to EGFP caused a significant increase in Ca2+ channel current density along with modest changes to other biophysical properties. Depolarization of CRMP-2–EGFP overexpressing neurons elicited a significant increase in release in glutamate compared to control neurons. Toxin block of Ca2+ entry via CaV2.2 abolished this stimulated release. The increased glutamate transmission was attributed to an increase in synaptic vesicle recycling by CRMP-2. CRMP-2’s effects on axonal length and branch complexity, important for establishing synaptic connectivity, were reduced by blocking Ca2+ influx via CaV2.2. Thus, the CRMP-2–Ca2+ channel interaction represents a novel mechanism for modulation of Ca2+ influx into nerve terminals and, hence, of synaptic strength.
__________________________________________________________________________________
May 20, 2009
Christian C. Felder, Ph.D.
Neuroscience Division, Eli Lilly and Company
2009 Gill Symposium, May 20, 2009, 10:00 a.m., Indiana Memorial Union, Whittenberger Auditorium
Title: Muscarinic acetylcholine receptors: A potential novel approach for the treatment of schizophrenia
Abstract:
Muscarinic receptors play a role in regulating both the dopamine and glutamate systems which are key neurotransmitter systems disrupted in schizophrenia. The five muscarinic acetylcholine (M1-M5) receptors were cloned beginning in 1986, yet development of subtype selective ligands has lagged well behind molecular characterization of both structure and function of this receptor family. Historically, acetylcholine mimetics based on arecoline provided modest functionally selective agonists which were advanced into clinical development for symptomatic treatment of Alzheimer’s disease and schizophrenia. However, side effects linked primarily to parasympathetic drive prevented successful launch of a muscarinic agonist therapeutic. Despite these challenges, positive proof of concept data was generated in both Alzheimer’s disease and schizophrenia. Additional knowledge of muscarinic receptor subtype physiology was gleaned primarily from experiments with knockout mice bearing genetic deletion of each muscarinic receptor subtype. More recently, highly selective agonists and positive allosteric modulators have been described for the M1 and M4 receptors. This presentation will focus on the discovery and preclinical development of a selective positive allosteric modulator for the muscarinic M4 receptor targeted for the symptomatic treatment of schizophrenia.
__________________________________________________________________________________
May 20, 2009
Aina Puce, Ph.D.
Indiana University Department of Psychological and Brain Sciences
2009 Gill Symposium, May 20, 2009, 2:30 p.m., Indiana University, Whittenberger Auditorium
Title: The neural basis of social cognition
Abstract:
The study of social interactions under naturalistic and dynamic conditions is a holy grail with regard to understanding how the brain processes meaningful, but fleeting, socially relevant information. To this end, multimodal imaging confers many advantages by capitalizing on the various strengths of the different assessment techniques. I will present data from functional MRI studies and scalp electrophysiological ERP studies that relate social cognition - the study of understanding the actions and intentions of others. Importantly, fMRI can identify the active brain structures in a social cognition task, whereas ERP studies are excellent at delineating the timing of these processes. One approach is to combine the data from both methods to give a more complete picture of the working human brain. I will contrast perceptual neural responses to socially relevant and seemingly irrelevant face and body movements from those related to higher order social and affective processing. Additionally, I will examine how important it is to control low-level stimulus variables in order to study social cognition, and how robust data can be obtained with both explicit and implicit manipulations of social cognition. Finally, I will discuss some approaches for future studies which will use single-trial neuroimaging and behavioral approaches.Supported by R01 NS049436.
_________________________________________________________________________________
April 29, 2009
Eva Anton, Ph.D.
UNC School of Medicine
4:00 p.m. in the Psychological and Brain Sciences Building, PY101
Title: Mechanisms of neuronal placement and differentiation in the developing cerebral cortex
________________________________________________________________________________
April 22, 2009
Klaus-Armin Nave, Ph.D.
Max Planck institute of Experimental Medicine
4:00 p.m. in the Psychological and Brain Sciences Building, PY101
Title: Axon-glia interactions and mouse models of human myelin disease
Abstract:
The long-term integrity of axons is a bottleneck for the function of the nervous system, as illustrated by many several neurodegenerative diseases. Oligodendrocytes and Schwann cells myelinate long axons for rapid impulse conduction, but other important functions of these axon-associated glial cells exist that remain poorly understood. We have identified genes expressed exclusively in mature oligodendrocytes, such as Plp1 and Cnp1, that are not essential for myelination, yet required the long-term survival of axons. The role of ensheathing glia in preserving axonal integrity also involves peroxisomes that are often localized at sites of axon-glial contact. Loss of peroxisomal functions in oligodendrocytes of conditional Pex5 mutants causes axon loss in the white matter and a strong inflammatory response, with the infiltration of B and activated CD8(+) T cells. The model is discussed that oligodendrocytes provide a neuroprotective function against both axonal degeneration and neuroinflammation, which is relevant for human neurological diseases, such as multiple sclerosis.
_________________________________________________________________________________
April 15, 2009
Tibor Harkany, Ph.D.
University of Aberdeen School of Medical Sciences and the Karolinska Institutet
4:00 p.m. in the Psychological and Brain Sciences Building, PY101
Title: Endocannabinoid signaling during brain development
Abstract:
Endocannabinoids (eCB) function as retrograde messengers at both excitatory and inhibitory synapses, and control various forms of synaptic plasticity in the adult brain. The molecular machinery required for specific eCB functions during maintenance of synaptic homeostasis is becoming well established. However, eCB signaling plays surprisingly fundamental roles in controlling the acquisition of neuronal identity during CNS development. Recent work suggests that selective recruitment of regulatory signaling networks to CB1 cannabinoid receptors dictates neuronal state-change decisions. In addition, the spatial localization and temporal precision of eCB action emerges as a novel organizer in developing neuronal networks. At the moment, we are far from understanding the molecular logic and chronodynamics of how eCB signaling networks specify in the embryonic brain, and how their specific neurodevelopmental functions relate to and define their retrograde control of neurotransmitter release at mature synapses. Important open questions include: where and when eCBs are produced in the developing brain; the molecular identity of eCBs and whether they represent ‘active’ signals; whether respective receptors and intracellular signal transduction cascades differ from those in the postnatal brain; how eCB signaling integrates with other regulatory systems; and how the relative power of this newly-emerging signaling entity contributes to define neurodevelopmental processes. In this talk, I will summarize contemporary discoveries establishing eCB-driven cellular identification events in the developing cerebrum, and define a unifying concept of how eCB signaling provides positional signals for excitatory and inhibitory afferents along the dendritic tree of cortical neurons, thus shaping the complexity of cortical connectivity.
_______________________________________________________________________________
April 08, 2009
D. James Surmeier, Ph.D.
Northwestern University
4:00 p.m. in the Psychological and Brain Sciences Building, PY101
Title: To go or not to go: dopaminergic modulation of striatal synaptic plasticity
Abstract:
At synapses between cortical pyramidal neurons and principal striatal medium spiny neurons (MSNs), postsynaptic D1 and D2 dopamine (DA) receptors are postulated to be necessary for the induction of long-term potentiation and depression, respectively – forms of plasticity thought to underlie associative learning. Because these receptors are restricted to two distinct MSN populations, this postulate demands that synaptic plasticity be unidirectional in each cell type. Using brain slices from DA receptor transgenic mice, we show that this is not the case. Rather, DA plays complementary roles in these two types of MSN to ensure that synaptic plasticity is bidirectional and Hebbian. In models of Parkinson’s disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms.
_____________________________________________________________________________
March 25, 2009
Jeffrey Mogil, Ph.D.
McGill University
4:00 p.m. in the Psychological and Brain Sciences Building, PY101
Title: Pain, Sex and Your Mother
Abstract:
Pain researchers have now come to some consensus regarding the existence of small quantitative sex differences in the sensitivity to and tolerance of pain in humans. Differences in the effectiveness of analgesics in men and women are also appreciated. However, broad conclusions regarding the existence and direction of such sex differences are complicated by emerging evidence from laboratory animals that sex differences interact with genetic background. That is, male and female mice of only certain genetic backgrounds display sex differences. Even the direction of sex differences (male>female vs. female>male) may depend on genetic factors. In addition to these quantitative sex differences, evidence is rapidly emerging that the sexes may differ qualitatively in their neural processing of pain and analgesia. That is, different neural circuits, transmitters, receptors and genes may be relevant to pain modulation in males and females. I will present data from our laboratory and others demonstrating that the specific genetic and neurochemical mediation of analgesic mechanisms in male and female mice are radically different. More recent experiments in my laboratory pertain to the other meaning of “sex and pain.” We are studying the effect of pain itself on sexual behavior in male and female mice using standard and “paced” mating paradigms.
_____________________________________________________________________________
October 15, 2008
Margaret M. McCarthy, Ph.D.
University of Maryland School of Medicine
4:00 p.m. in the Psychological and Brain Sciences Building, PY101
Title: Multiple Mechanisms, One Goal – Sexual Differentiation of the Brain
Abstract:
The Organizational / Activational Hypothesis established 50 years ago that enduring sex differences in brain and behavior are established by the actions of gonadal steroids early in life. What has been lacking is a mechanistic understanding of how steroids permanently alter the neuronal architecture to induce sex differences in adult physiology and behavior. Our research group has begun to make in-roads in this area and have discovered a surprising role for prostaglandins, as well as more ubiquitous neurotransmitters such as GABA and glutamate. We have also determined that cell-to-cell communication, frequently involving astrocytes and neurons, is a common principle and yet, the precise mechanism of steroid-mediated differentiation of the brain is regionally specific. The net result of divergent mechanisms of the same steroid is the creation of a wider variety of phenotypic outcomes than could be achieved by a uniform mechanism across all brain regions. Understanding the mechanistic basis of steroid action on the developing brain will provide insight into potential sites of prevention or intervention for the many gender-biased neurological and mental health disorders with developmental origins.
October 10, 2008
Johannes W. Hell, Ph.D.
Professor, Department of Pharmacology
University of Iowa
2:30 p.m. in the Chemistry Building, CH033
Title: The role of NR2B phosphorylation by calcium/calmodulin kinase II in learning and memory
Abstract:
We are studying the assembly and function of signaling complexes at synapses, the contact points between neurons that mediate synaptic transmission. A period of heightened activity leads to a permanent upregulation of synaptic transmission at individual synapses. This physiological phenomenon known as long-term potentiation or LTP is thought to underlie learning and memory. We found earlier that the two key players in LTP induction, the NMDA-type glutamate receptor and the calcium-and calmodulin-dependent kinase CaMKII, interact with each other, strategically placing CaMKII next to the source of calcium influx that activates the kinase and also next to the postsynaptic substrates important for LTP. We identified single residues that are critical for CaMKII binding to the NMDAR. Knock-in mice with point mutations that inhibit CaMKII binding to the NMDAR show normal basal synaptic function but reduced LTP and impaired memory formation.
September 17, 2008
Nephi Stella, Ph.D.
University of Washington School of Medicine
4:00 p.m. in the Psychological and Brain Sciences Building, PY101
Talk title: Targeting enzymes that hydrolyze endocannabinoids for the treatment of neurodegenerative diseases
Abstract:
Microglial cells, the macrophages of the brain, play a key role in the control and propagation of neuroinflammation. It is known that microglia produce endocannabinoids and express CB2 receptors, and that 2-AG stimulates microglial cell migration through CB2 receptors. Although endocannabinoid-hydrolyzing enzymes constitute a promising therapeutic target and their inhibition in microglia is likely to control neuroinflammation response and propagation, little is known about their expression in these immune cells. We have previously shown that the microglial cell line BV-2 expresses a novel, uncharacterized 2-AG-hydrolyzing enzyme. Here, in collaboration with the Cravatt laboratory, we performed an activity-dependent protein profiling of the serine hydrolase activities expressed by BV-2 cells and identified three novel 2-AG-hydrolyzing enzymes: ABHD6, ABHD12 and NTE. Using both a pharmacological approach and shRNA knockdown, we show that ABHD6 constitutes a major player in the control of 2-AG hydrolysis and bioactivity in BV-2 cells. We found that ABHD6 activity is also important in controlling 2-AG hydrolysis and bioactivity in neurons. Finally, we found a transient down-regulation of ABHD6 mRNA in the striatum of R6/2 mice, a model of Huntington’s Disease, as a function of disease progression. These results suggest that ABHD6 constitutes a novel component of the endocannabinoid signaling system and may represent a promising target for the control of neuroinflammation occurring in neurodegenerative diseases.
October 22, 2007
Cary Lai, Ph.D.
The Scripps Research Institute
"Neuregulin-ErbB Signaling in the Nervous System.”
4:00 p.m. in the Kelley School of Business, CG 1008
Abstract: Our laboratory is studying the role of the receptor tyrosine kinases, the “ErbBs” (ErbBs 1-4) and their ligands, the “neuregulins” (NRGs 1-4) in the mature and developing nervous system. NRG1 is best known as a key regulator of Schwann cell function and as a regulator of acetylcholine receptor (AChR) expression in muscle cells in vitro. Our primary focus has been the analysis of conditional knockout mice that lack ErbB4 in the nervous system and on the production of transgenic mice that permit the regulated expression of NRG1. Our studies have revealed that ErbB4 is expressed by multiple populations of tangentially migrating neuronal precursors. During development, ErbB4 marks the migrating interneuronal precursors as they move from the ganglionic eminences to the cortex and hippocampus. In mature mice, ErbB4 is expressed by cells in the rostral migratory stream (RMS), the primary site of neurogenesis in the adult rodent brain. The RMS contains interneuronal precursors that are born in the subventricular zone near the lateral ventricle and that migrate to the olfactory bulb. In both populations of cells, the loss of ErbB4 leads to a reduction in the number of interneurons and to deficits in migration. A preliminary behavioral characterization of ErbB4-deficient mice has revealed a a reduction in anxiety-like behavior. As ErbB4 is expressed at high levels in the intercalated cells of the amygdala, we are testing the hypothesis that a loss of ErbB4 function in this region may be responsible for this behavioral alteration. We are also evaluating neuregulin function by establishing lines of transgenic mice that permit the regulated expression of 3 isoforms of NRG1 (I, II and III). We have developed a system permitting expression in cholinergic neurons, through the use a bacterial artificial chromosome (BAC) encoding choline acetyltransferase. Temporal regulation is provided by the tetracycline system. These mice should allow assessing the plasticity of the myelination process, should permit testing the role of NRG1 as a regulator of AChR expression at the neuromuscular junction in vivo, and should facilitate an understanding of how NRG1 affects neuronal function in the CNS. As NRG1 has been identified as a susceptibility gene for schizophrenia, mice permitting inducible expression of NRG1 should help to assess the role of this factor in a number of pathways implicated in this process including defects in cell migration, neurotransmitter receptor expression, interneuronal function and myelination.
February 19, 2007
Wayne D. Bowen, Ph.D.
Brown University
"Sigma-2 Receptor-Mediated Apoptosis in Human SK-N-SH Neuroblastoma Cells."
4:00 p.m. in the Psychological and Brain Sciences Building , PY101
Abstract: Sigma receptors comprise a novel family of pharmacologically-defined receptor sites that recognize several important classes of psychotropic drugs. These include typical neuroleptics such as haloperidol, the psychotomimetic agent phencyclidine (PCP), some synthetic opiates such as pentazocine, and some psychostimulants like cocaine. Sigma-1 and sigma-2 receptor subtypes are currently known. In addition to expression throughout the CNS, these receptors are found in peripheral tissues and are highly expressed in tumor cell lines of various tissue origins. We have shown that sigma-2 receptor agonists induce apoptotic cell death in both tumor cell lines and in primary neuronal cells. We have explored the signaling pathway in human SK-N-SH neuroblastoma cells in some detail. Treatment of these cells with the sigma-2 subtype selective agonist, CB-64D results in caspase-dependent cell death via a mechanism that is dependent upon mitochondrial depolarization. The Bcl 2 -family protein, Bid, is cleaved in a caspase-dependent manner. Truncated Bid (tBid) is known to promote mitochondrial depolarization. We also show that several apoptogenic factors are released from mitochondria. Apoptosis inducing factor (AIF) and endonuclease G (Endo-G) are released upon treatment with sigma-2 agonist and translocate to the nucleus. Cytochrome C is released into the cytosol. Release of these factors is dependent upon Bid cleavage and is blocked by caspase inhibitors. Taken together, the data suggest that sigma-2 receptors activate caspase-dependent Bid cleavage to depolarize mitochondria, causing release of AIF, Endo-G, and cytochrome C, which ultimately leads to cell death. Caspase activation may be related to the ability of sigma-2 agonists to increase cellular ceramide levels in these and other cells. Sigma-2 receptor-mediated apoptosis could play a role in induction of the tardive dyskinesias occurring in patients treated chronically with typical neuroleptics and may also be exploited in the development of novel antineoplastic agents effective against a wide variety of cancers.
November 29, 2006
Cary H. Lai, Ph.D.
The Scripps Research Institute
"The Many Wonders of Neuregulin-ErbB Signaling in the Nervous System ."
12:00 p.m. in the Indiana Memorial Union, State Room East
Abstract: The neuregulins (NRG1-4) are a family of polypeptide growth factors that bind to and activate members of the transmembrane protein-tyrosine kinases known as the “ErbBs” (ErbB1-4). The interest in neuregulin biology has increased as a result of the identification of the NRG1 gene as a susceptibility factor for the neuropsychiatric disorder schizophrenia. Given the significance of this association, just what does NRG1 do in the brain? The current evidence suggests that NRG1 appears to be involved in a dizzying array of processes, many of which have been implicated as factors contributing to the development of this disorder. NRG1 has been shown to serve as a key regulator of myelination in the peripheral nervous system and may also influence this process in the CNS. Neuregulin signaling through ErbB4 has been observed to alter the migration of interneuronal precursors and may modulate their function in the mature nervous system. NRG1 has also been shown to regulate the expression of neurotransmitter receptors, and hence is capable of affecting synaptic function. In addition, recent studies have provided evidence that both NRG1 and ErbB4 engage in “back-signaling”, where the cytoplasmic tails of these molecules can enter the nucleus and influence transcription. Although the other neuregulins expressed in the brain, NRG2 and NRG3, have not been linked to schizophrenia, the ability of these molecules to activate ErbB signaling suggests that we are yet to uncover additional functional roles for neuregulin-ErbB signaling in the nervous system.
October 25, 2006
Jae Young Seong, Ph.D.
Korea University College of Medicine
"Orphan G-Protein Coupled Receptors: Emerging Targets for Drug Development”
The superfamily of G protein-coupled receptors (GPCRs) is the largest and most diverse group of membrane-spanning proteins. It plays a variety of roles in pathophysiological processes by transmitting extracellular signals to cells via heterotrimeric G proteins. Completion of the human genome project revealed the presence of ~ 168 genes encoding established transmitter GPCRs, as well as 207 genes predicted to encode novel GPCRs for which the natural ligands remained to be identified, the so-called ‘orphan' GPCRs. Eighty-seven of these orphans have now been paired to novel or previously known molecules, and 120 remain to be deorphaned. Since known GPCRs have often been successfully used as therapeutic targets, orphan GPCRs may serve as a rich source of potential targets for drug discovery. For several years, we have attempted to elucidate the mechanism underlying the ligand-receptor interaction and signal transduction of GPCRs for many neuropeptides such as gonadotropin-releasing hormone, oxytocin/vasopressin, and neurotensin. Accumulation of this research experience allows us to develop a novel high throughput assay system to screen novel compounds acting at orphan GPCRs. Using this system, we found that orphan GPR92 responds to various lipid-derived molecules. As the mRNA and protein for GPR92 are largely expressed in the dorsal root ganglia, it is postulated that interaction of GPR92 with its ligands may be involved in sensory (particularly pain sensing) processes. The precise physiological role of GPR92 and its ligands in the sensory system, however, should be further elucidated.
October 26, 2005
Kenneth Mackie, M.D.
Professor, University of Washington
"Cannabis, cannabinoids, and THC: What’s all the buzz about?"
The desire to understand how cannabis produces its characteristic psychoactive effects has resulted in the discovery of a novel neuromodulatory network, the endocannabinoid system. This system is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that make and degrade endogenous cannabinoids. Neuronal cannabinoid (CB1) receptors appear to mediate the psychoactive effects of cannabis and its phytocannabinoids (such as delta-9 THC), as well as the neuronal effects of endocannabinoids. At the behavioral level, endocannabinoids are involved in processes as diverse as memory, movement, and analgesia. Emerging clinical data suggests that manipulations of the endocannabinoid system may be therapeutically beneficial. At the cellular level, endocannabinoids acting at CB1 receptors play a role in specific forms of long and short duration synaptic plasticity, and it is plausible that these cellular effects underlie the behavioral effects. The interactions of delta-9 THC with endocannabinoids likely underlie the psychoactive effects of cannabis, although emerging evidence suggests that this is not due to delta-9 THC merely “hijacking” and activating CB1 receptors.
June 2, 2005
David Van Vactor, Ph.D.
Associate Professor, Department of Cell Biology, Program in Neuroscience
DFCI/Harvard Cancer Center, Harvard Center for Neurodegeneration and Repair, Harvard Medical School
"Signaling Mechanisms that Control Axon Guidance Decisions."
Growth cone navigation relies upon active remodeling of actin and microtubule cytoskeletal arrays. Despite rapid progress in finding actin regulators downstream of various guidance receptors, little has been learned about signaling effectors that directly associate with microtubules. Here we identify the microtubule-associated protein Orbit/MAST as a component that cooperates with the Abelson (Abl) protein tyrosine kinase during axon guidance in the Drosophila embryo. At the midline, Orbit/MAST and Abl mutants exhibit identical phenotypes, suggesting a model where Abl acts a node to coordinate actin and microtubule dynamics downstream of Slit. Orbit/MAST displays strong genetic interactions with Slit and its Roundabout-family receptors, supporting this model. Orbit/MAST is expressed at high levels in the developing nervous system where it localizes to axons and growth cones. Higher resolution imaging of the Orbit/MAST ortholog CLASP in Xenopus growth cones suggests that this family of microtubule plus-end tracking proteins identifies a subset of dynamic microtubules that probe the actin-rich peripheral domain of the growth cone where guidance signals exert their initial influence on cytoskeletal organization.
March 2, 2005
Laurence F. Abbott, Ph.D.
Professor of Biology, Brandeis University
"Multi-Timescale Dynamics in Neural Systems."
Storing memories of ongoing, everyday experiences requires a high degree of plasticity, but retaining those memories demands protection against changes induced by further activity and experience. The standard model for memory storage involves switch-like transitions in the connections between neurons, induced by activity. Such a mechanism is good at storing but bad at retaining memories if the transitions are likely, and poor at storage but good at retention if they are unlikely. Statistical and mean-field calculations can quantify these effects, and they suggest that better performance can be obtained using multi-timescale dynamics. Professor Abbot presented a model based on a cascade of states governed by widely different time constants and showed that it combines high levels of memory storage with long retention times, significantly outperforming alternative models. The model accounts for previously unexplained aspects of the dynamics of learning and memory.
February 18, 2005
Steven Paul, M.D.
Executive VP, Science and Technology and President of Lilly Research Laboratories, Eli Lilly and Company
"Alzheimer's Disease: From Genes to New Drugs."
February 4, 2005
Phil Skolnick, Ph.D., D.Sc (hon)
Senior VP, Research and Chief Scientific Officer, DOV Pharmaceutical, Inc.
"Anxiety: Of Molecules, Mice, and Men."
Generalized anxiety disorder is the second most commonly diagnosed psychiatric illness in primary care settings. The lifetime prevalence of generalized anxiety disorder has been estimated at 5-6%, and should thus be considered a significant public health issue. Dr. Skolnick summarized c onverging lines of evidence that the neurotransmitter GABA ( g -aminobuytric acid), by signaling through GABA A receptors, modulates anxiety as well as the action of many useful anti-anxiety agents. Three main issues were presented: 1) a review of current thinking on the assembly and operation of GABA A receptors; 2) evidence that modulation of GABA A receptors produces anxiety-like behaviors in primates, including humans; and 3) prospects for the development of novel anxiolytics acting via GABA A receptors.
October 21, 2004
J. Troy Littleton, Ph.D., M.D.
Associate Professor of Neurobiology, The Picower Center for Learning and Memory, Massachusetts Institute of Technology
"Bidirectional Communication at Synapses: A Genetic Dissection of Synaptic Plasticity in Drosophila."
The computational power of the brain depends on synaptic connections that link together billions of neurons. Dr. Littleton's laboratory is interested in the mechanisms by which neurons form synaptic connections, how synapses transmit information, and how synapses change during learning and memory. Bernard Katz and colleagues established the hypothesis that calcium influx into the presynaptic nerve terminal triggers neurotransmitter release and the initiation of synaptic communication. Dr. Littleton's research group has used genetic and electrophysiological approaches at the Drosophila embryonic neuromuscular junction to characterize the molecular mechanisms that mediate calcium sensing and synaptic vesicle fusion at synapses. In particular, this group has shown that the calcium-binding synaptic vesicle protein Synaptotagmin 1 couples calcium influx to rapid and synchronous synaptic vesicle fusion. They have also identified a novel calcium-sensitive vesicular trafficking pathway that is present in the postsynaptic compartment that mediates retrograde signaling at synapses. This retrograde signaling pathway requires a distinct synaptotagmin isoform, Synaptotagmin 4, and mediates both plasticity induction and synaptic rewiring in response to activity. An important tenet for research into synaptic plasticity underlying memory formation is Hebb's postulate, which proposes that a synaptic connection is potentiated when the activity of the pre- and post-synaptic neurons are correlated, leading to structural changes in synaptic growth. Dr. Littleton and colleagues have performed a genetic dissection of synapse-specific potentiation and growth using the Drosophila glutamatergic neuromuscular junction. Their current findings indicate that calcium influx into postsynaptic cells induces secretion of retrograde signals from postsynaptic vesicles, activating a cAMP pathway in presynaptic terminals that modulates synaptic growth in a Hebbian input/output-specific manner.
