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Provided by Elsevier - PublisherNeuron, Connector Vol. 48, 201–211, October 20, 2005, Copyright ª2005 by Elsevier Inc. DOI 10.1016/j..2005.10.005 at Historical Perspective

Solomon H. Snyder* ing these talents and himself making major contribu- Department of Neuroscience tions to pathology. William Osler defined the field of in- School of Medicine ternal medicine, and William Halstead inaugurated 725 North Wolfe Street modern surgery. There was no Department , 21205 nor even a neurology division of Medicine. remained a subdivision of the surgery department for al- most 70 years till Donlin Long was appointed the direc- In 1979, Joshua Lederburg, recently appointed presi- tor of a new Neurosurgery Department. dent of Rockefeller University, was in recruiting mode. Based on his long-term interest in the and psychi- Neurosurgery and atry, Josh approached me with an attractive offer for In 1906, Harvey Cushing was appointed the first head of myself and my colleagues Joe Coyle and Mike Kuhar. neurosurgery at Hopkins (Figure 1). He revolutionized pi- I visited our Dean, Richard Ross, to say goodbye, as tuitary surgery and, by carefully monitoring symptoms I knew that Hopkins could never provide us Rockefeller- following removal of pituitary tumors, he was able to elu- like resources. While Ross couldn’t match the Rockefel- cidate the role of excess or deficient secretion of the an- ler offer for a professor, he had an alternative proposal. terior pituitary and to confirm his clinical observations Years earlier, an advisory committee had recommended with studies in animals (Cushing, 1909). He showed that Hopkins establish a Department of Neuroscience. that hormonally active tumors arising in young people Dr. Ross suggested a mini-department comprised to gigantism and, in adults, to acromegaly. solely of myself, Coyle, and Kuhar, which might integrate Walter Dandy succeeded Cushing as head of the neu- Hopkins neuroscience. In contrast to the tens of millions rosurgery division. In 1913, he elucidated the circulation of dollars provided nowadays as dowries for new de- of cerebrospinal fluid (CSF), showing how selective partmental directors, the Dean offered only a modest blockade to hydrocephalus (Dandy and Blackfan, annual budget that could be ‘‘saved’’ for the three years 1913). In dogs, obstructing the Sylvian Aqueduct caused till a single floor would become available for our depart- dilation of the third and lateral ventricles, while blocking ment. Dan Nathans, Director of Microbiology and a val- the Foramen of Monro elicited a similar ballooning of the ued confidant, advised that a new department must be lateral ventricle. In the same study, he provided the first done ‘‘right’’ so I should ask for triple the offered space. definitive evidence that the choroid plexus elaborates The Dean agreed, and on July 1, 1980, our department CSF, as its removal prevented hydrocephalus. He dis- commenced operations. Today, Neuroscience is the covered how CSF is absorbed into subarachnoid blood largest basic science department at Hopkins. Our fac- vessels. He extended this basic research into patients, ulty has done well. Among present and emeritus mem- observing that every case of ‘‘idiopathic hydrocephalus’’ bers, three of our primary faculty have been elected to was associated with obstruction of the Sylvian Aque- the National Academy of Sciences, four are fellows of duct or one of the critical foramina. the Academy of Arts and Sciences, two of the American Even more important was Dandy’s development Philosophical Society, two have received the Lasker in 1918 of pneumoencephalography, conceptualized Award, two the National Medal of Science, and various when he noticed in the chest X-ray of a patient with a per- faculty members have accumulated more than 13 hon- forated intestine, free air outlining the structure of vari- orary doctorates. Science citation analysis indicates ous abdominal viscera. Might injected air outline the ce- that of the eight most highly cited Johns Hopkins medi- rebral ventricles? In short-order he injected gas into the cal , five are appointed in our department. For cerebral ventricles, inaugurating pneumoencephalogra- the decade 1989–1998, four of the world’s 16 most phy, which, until the advent of CAT scans, remained the highly cited were from Hopkins, with most powerful means of identifying brain tumors and no other institution having more than one. other abnormalities (Dandy, 1918). But neuroscience at Hopkins did not begin in 1980. Systems neuroscience began with operative ablation Johns Hopkins has a long tradition of contributions in of various brain regions to mimic abnormalities associ- the field. More than most other institutions, Hopkins’ ef- ated with brain tumors or surgical removal of brain tis- forts in the encompass clinical as well as sue to cope with injuries or . Phillip Bard, the basic science. Let me relate some of these in a brief pan- fourth Director of Physiology at Hopkins, arrived in Bal- orama that is not meant to be exhaustive but merely to timore in 1933 following training at Harvard with Walter illustrate a few major themes, especially the breadth of Cannon. Work in Cannon’s laboratory had revealed research and the uniquely collegial relationships of Hop- that disconnecting the from the brain- kins neuroscientists. stem of cats elicited rage responses. As these responses were not associated with ‘‘real’’ anger and were not di- Early Days rected toward the triggering , they were desig- The founding fathers of Hopkins were giants in American nated ‘‘sham rage.’’ At Hopkins, Bard attempted to local- medicine, with William Welch, the first Dean, orchestrat- ize the specific brain regions responsible for sham rage. After decorticating cats to elicit rage, he made various transactions through the brain stem. Successive trans- *Correspondence: [email protected] actions in a caudal direction failed to alter sham rage Neuron 202

recordings would be critical. In 1933, Ralph Gerard, working at the University of Chicago, had identified cere- bral action potentials, and, with Wade Marshall, he em- ployed this approach to characterize sensory activity in the cerebral cortex. In the late 1930s, Marshall moved to Hopkins, and, with Bard and Clinton Woolsey, he de- veloped technology for measuring evoked cortical po- tentials and mapped the sites for cutaneous touch sensation on the primate postcentral gyrus (Marshall et al., 1937). Vernon Mountcastle, Bard’s successor in 1964 as Di- rector of Physiology, took up the challenge of mapping the somatic sensory system with greater refinement. In the mid-1950s, utilizing newly developed microelectro- des that permitted single-cell recoding, Mountcastle discovered that submodalities of touch and pressure sensation were localized to vertical columns running from the surface of the brain to underlying white matter. All cells in an individual column responded to selective sites on the skin and to either superficial or deep pres- sure (Mountcastle, 1957). This columnar organization is now appreciated as a universal organizing principle of brain function. At about the same that Mountcastle was doing his pioneering work in the Physiology Department, Ste- phen Kuffler spent 12 years in a laboratory in the base- ment of the Ophthalmology Department. In one body of work, he characterized synaptic inhibition in stretch of crustacea, which led to subsequent work of his later colleagues David Potter and establishing GABA as the principal inhibitory neurotransmitter. Perhaps Kuffler’s most important con- tribution was his discovery of center-surround inter- actions in the retina (Kuffler, 1952). Utilizing a multibeam ophthalmoscope that had been developed in the Ophthalmology Department, he recorded from single retinal ganglion cells and observed diametrically oppo- site responses depending on whether light impacted the central or peripheral field. In 1959, Kuffler moved Figure 1. Johns Hopkins’ Neuroscience Greats to Harvard where in 1966 he established a Department (A) Harvey Cushing (left), the first head of Neurosurgery, provided of Neurobiology. the definitive characterization of hypo- and hyperpituitarism. Walter Torsten Wiesel and David Hubel joined Kuffler at Hop- Dandy (right), his successor, developed ventriculography, inaugu- kins in the mid-1950s, initially working on the retina and rating the field of clinical brain imaging. then turning their attention to the visual cortex. They dis- (B) Philip Bard (left) localized brain areas mediating ‘‘rage’’ and em- covered center-surround and other organizational prin- ployed evoked potentials to map sensory sites in the brain. Vernon Mountcastle (right), using microelectrode recordings, discovered ciples in the cortex (Hubel and Wiesel, 1959). Most the columnar organization of brain function. importantly, they detected parallel receptive fields for (C) Ross Harrison (left) inaugurated the field of tissue culture using neighboring cells in the visual cortex, pointing to a uni- frog embryonic . David Bodian (right) employed culture versal role for Mountcastle’s concept of columnar orga- to differentiate diverse types of polio virus, laying the groundwork nization of the cerebral cortex. They moved with Kuffler for the polio vaccine. to Harvard in 1959 where they continued their elegant (D) John Jacob Abel (left), founding Director of the Department of and Experimental Therapeutics, isolated epineph- assessment of how visual information is organized in rine as the of the and subsequently ob- the cortex, leading to their receipt of the Nobel Prize tained the first crystals of insulin. Curt Richter (right) delineated for Physiology or Medicine in 1981. systemic physiologic regulation by the biologic clock. provides the ultimate systems approach to the brain and behavior. Adolph Meyer was the first Di- until he cut through the posterior . rector of Psychiatry at Hopkins. In the Henry Phipps Directed posterior hypothalamic lesions eliminated Psychiatric Clinic, which opened in 1913, Meyer inaugu- sham rage, while electrical stimulation in this region rated an unprecedented approach to psychiatry with caused rage. This work lead to conceptualizations of laboratories of , , and emotional behavior determined by the limbic system of behavior and a clinical program that emphasized a com- brain structures. prehensive approach to each patient integrating psy- Bard soon realized that behavioral observations were chological and biological factors, an essentially new dis- insufficient to clarify brain function and that electrical cipline that he dubbed ‘‘psychobiology’’ (Meyer, 1915). Historical Perspective 203

Among the early scientists Meyer recruited was John technique used by John Enders for his Nobel Prize-win- Watson, the founder of behaviorism. Watson did not re- ning cultivation of the polio virus. main long at Hopkins, his principal contribution being The crucial research for growing polio virus in tissue his graduate student Curt Richter who, when Watson culture took place at Johns Hopkins in the laboratory left, took over the laboratory and remained in it for about of David Bodian, who also employed some of Gey’s pro- 70 years. cedures. Bodian was able to differentiate nerve cells that Among his many contributions, Richter developed were resistant or sensitive to viral infection, laying the precise means for monitoring all aspects of a rat’s life groundwork for much polio vaccine research (Bodian, in a laboratory using a cage containing a running wheel 1955). At that time, large numbers of viral strains had to assess temporal aspects of activity initiation. With been identified, but it wasn’t clear which were relevant this simple but elegantly powerful system, Richter ex- for vaccine development. Bodian established that there plored the molecular and neuroanatomical regulation were only three major immunologic forms of the virus, of the ‘‘biological clock’’ (Richter, 1960). In 1965, when permitting development of a practical vaccine. I arrived at Johns Hopkins for psychiatry residency, Besides his work on the polio virus, Bodian, who one of my first visits was to Richter’s laboratory. I had served as Director of the Anatomy Department, was worked with Julie Axelrod at the NIH on circadian one of the world’s great neuroanatomists. Utilizing his rhythms in the content of the pineal technique, the ‘‘Bodian Stain,’’ he identified and sought Richter’s advice. He showed me his experi- the existence of neurofilaments. Because of his interest ments making discrete brain lesions to localize the in spinal cord defects in polio, he focused on the ultra- clock, which he had narrowed down to a small area in structure of neurons in the spinal cord and was the first the hypothalamus. Because of his obsessive drive to to obtain strong evidence that spherical synaptic vesi- ‘‘be sure’’ of his results, he did not publish these find- cles were associated with excitation and flat vesicles ings, although his lesions, in the vicinity of the supra- with synaptic inhibition (Bodian, 1966). chiasmatic nucleus, anticipated the discovery years John Jacob Abel founded the Department of Pharma- later by Robert Moore of this nucleus as the locus of cology at Hopkins. Based on his strong background in the mammalian ‘‘clock.’’ chemistry, Abel attempted to isolate biologically active Richter’s contributions were remarkably diverse. For substances. One of his first triumphs was the identifica- instance, he pioneered the notion that rodents will self- tion of as the hormone of the adrenal me- select an optimal diet and, in this way, he established dulla (Abel and Crawford, 1897). Much later in his career, the minimal daily requirement for and minerals he obtained the first crystals of insulin, establishing its (Richter et al., 1938). His work on the galvanic skin protein nature (Abel, 1926). As with some of the other response was critical in the evolution of the lie detector early departmental directors at Hopkins’, Abel set test. standards for the rest of the country. He regarded phar- W. Horsley Gantt, a contemporary of Richter’s in the macology primarily as a medical discipline and so never Psychiatry Department, studied with Ivan Pavlov and trained Ph.D. students, with Hopkins finally establishing was a pioneer in introducing Pavlovian psychiatry into a pharmacology graduate program under my initial the . He utilized Pavlov’s techniques to de- direction in 1968. Abel’s national influence was evi- velop models of mental illness in dogs. For his contribu- dent in his founding the Journal of Pharmacology and tions, he received a Lasker Award in 1946, the inaugural Experimental Therapeutics and the Journal of Biological year of these prizes. Chemistry. Clinical played an important role Cellular, Molecular, and Pharmacologic Research at Hopkins. In the late 1940s, Leslie Gay, who directed Today, most cellular- research the allergy clinic, was treating a lady for hives with anti- employs tissue culture as routine methodology. The first . She mentioned that her severe motion sick- successful use of tissue culture employed neurons and ness evaporated when she took the new antihistamine. was carried out at Johns Hopkins by Ross G. Harrison Working through the auspices of Army Chief of Staff (Harrison, 1907). At the time of this research in 1907, General Omar Bradley, Gay directed the most sophisti- the cellular source of neuronal fibers was not at all clear. cated clinical drug trial of that era, a randomized study Harrison placed small portions of frog embryo spinal of 1500 soldiers on a north Atlantic trip to Europe. He cords in lymph on a microscope slide and was able to showed definitively that the antihistamine, Dramamine, observe clearcut neuronal sprouting. In 1917, the Nobel both prevented and relieved sea sickness (Gay et al., Prize Committee voted to award the prize in Physiology 1949). or Medicine to Harrison but ultimately did not award In 1954, Louis Lasagna, Hopkins’ first Head of Clinical a prize that year. Research underlying the Nobel Prize Pharmacology, discovered a novel approach to creating in 1956 for the growth of polio virus in kidney cell cul- less-addicting . He was investigating interac- tures did employ Harrison’s methodology. tions in humans of and antagonists, spe- Harrison’s innovations in tissue culture at Hopkins cifically and nalorphine. As a control, he ad- were continued by George Gey (Gey et al., 1952). Utiliz- ministered nalorphine alone and was astounded to ing a cervical tumor from Henrietta Lacks, Gey created detect efficacy equivalent to that of morphine the HeLa cell line, which to this day is the most widely (Lasagna and Beecher, 1954). Thus, nalorphine was employed tissue culture preparation and was particu- a mixed -antagonist. Its antagonist properties larly valuable for growing the three types of polio virus. decreased addictive propensities leading to major ef- Gey made myriad advances in tissue culture, including forts in the pharmaceutical industry to develop mixed the use of collagen as substratum and the roller-tube agonist-antagonist opiates as safer . Drugs Neuron 204

that emerged from this program, such as pentazocine neuroleptics in blocking receptors predicts and buprenorphine, remain the least-addictive commer- their antipsychotic actions. binding permitted cially marketed opiates. clarification of and hypotensive side effects of neuroleptics and . In his Modern Era own laboratory, Kuhar developed ligand-binding techni- I came to Johns Hopkins for psychiatry residency in ques for autoradiography, permitting him to localize opi- 1965 and, during the second year of residency, was ap- ate and other neurotransmitter receptors at a micro- pointed a full-time Assistant Professor of Pharmacology scopic level and to explain with reasonable precision while still a full-time psychiatry resident. At that time, most of the therapeutic and adverse effects of opiates systems neuroscience was a dominant presence in the (Young and Kuhar, 1979). Subsequently, in collaboration Department of Physiology, directed by Vernon Mount- with Henry Wagner, Chair of the Division of Nuclear castle. David Bodian, the Director of Anatomy and him- Medicine, he participated in the first imaging of neuro- self a distinguished neuroanatomist, had recruited nu- transmitter receptors in by PET scanning, merous neuroanatomists to his department. Neither technology subsequently employed with virtually all nor neuropharmacology existed at Hop- neurotransmitter receptors (Wagner et al., 1983). kins. After I completed psychiatry residency in 1968 and Coyle and his students employed receptor pharma- was promoted (Associate Professor, Pharmacology and cology to develop selective brain lesions. Following re- Psychiatry; 1970 Full Professor), Paul Talalay, Director ports that the rigid glutamate derivative kainate destroys of Pharmacology, appointed new faculty in a nascent neurons by , Coyle employed kainate le- ‘‘division’’ of neuropharmacology. These included Mi- sions to destroy cell bodies in the caudate/, chael Kuhar, my first graduate student, who did post- eliciting a model of Huntington’s disease (Coyle and doctoral training at Yale with , and Schwarcz, 1976). He utilized similar kainate lesions in Joseph Coyle, my first medical student trainee and sub- the of Meynert to establish that these sequently Research Associate with Julie Axelrod. Elliott cells are the source of the major innervation Richelson, a Hopkins medical student who had worked of the cerebral cortex. In collaboration with Peter White- with me and was subsequently an NIH Research Associ- house, Donald Price, and Mahlon DeLong in Neuropa- ate with Marshall Nirenberg, was for a few years a mem- thology and Neurology, he delineated the loss of the ber of our division. cholinergic projection to the brain in Alzheimer’s disease Early research in my laboratory with Coyle and Kuhar (Whitehouse et al., 1982). This work provided part of the focused on neurotransmitter uptake. Axelrod had estab- background for the subsequent use of lished by sympathetic nerve endings of norepi- inhibitors in treating the loss of Alzheimer’s nephrine as the mode of its synaptic activation in experi- disease. ments utilizing injections of radiolabeled Other important work on cholinergic transmission was into rodents. To study transmitter uptake in vitro and taking place in the laboratory of Daniel Drachman in the examine its kinetic properties, we sought to employ iso- Neurology Department. Drachman had long been in- lated nerve endings, . However, synapto- terested in the pathophysiology of myasthenia gravis. somes could only be prepared in sucrose solutions, As cholinesterase inhibitors were therapeutic, it was while an ionic environment was required for transmitter assumed that something about cholinergic uptake. As a medical student, Coyle devised a simple was abnormal. Once it was possible to measure nico- solution to this dilemma, homogenizing the brain first tinic cholinergic receptors with radiolabeled a-bungaro- in hypertonic sucrose and then adding ionic buffers toxin, Drachman and Douglas Fambrough in the with the sucrose protecting the synaptosomes from Department at Hopkins demonstrated a profound degradation. This system permitted the evaluation of depletion of cholinergic receptors in muscle biopsies numerous putative neurotransmitters, especially the of patients (Fambrough et al., 1973). At about the same demonstration that amino acids that seemed to be time, others showed that rodents that were immunized good candidates as neurotransmitters, glutamate, as- with nicotinic cholinergic receptors develop symptoms partate, and (in the spinal cord), possessed resembling myasthenia gravis. Drachman injected se- high-affinity sodium-requiring uptake systems which rum of myasthenic patients into mice and reproduced were not evident for ‘‘ordinary’’ amino acids (Logan symptoms of the disease, establishing myasthenia gra- and Snyder, 1971). At the Lilly Research Laboratories, vis as an autoimmune disease associated with degrada- David Wong adopted this crude synaptosomal prepara- tion of cholinergic receptors (Toyka et al., 1977). tion to screen drugs for selective inhibition of serotonin A major body of work in /Neurology versus norepinephrine uptake, permitting the discovery was carried out by Donald Price and Sangram Sisodia, of fluoxetine (Prozac) (Wong et al., 2005). elucidating mechanisms of amyloid b- formation In 1973, utilizing simple reversible ligand-binding in Alzheimer’s disease. They employed elegantly de- techniques with crude brain membranes, we were able signed transgenic mice to establish how mutations of to identify opiate receptors in the (Pert the amyloid precursor protein and its processing en- and Snyder, 1973). We extended this finding to recep- zymes elicit Alzheimer’s pathology (Price et al., 1998). tors for numerous neurotransmitters by seeking drugs They employed similar strategies to clarify the role of with high affinity and selectivity for receptors and ob- certain types of superoxide dismutase in amyotrophic taining from our valued collaborators at the New Eng- lateral sclerosis. land Nuclear Corporation (now Perkin-Elmer) tritiated The Department of Biomedical Engineering has al- versions of the drugs (Snyder, 2002). Such studies per- ways housed distinguished neurophysiologists with mitted the demonstration that the relative potencies of special expertise in auditory and vestibular studies. Historical Perspective 205

Figure 2. Primary Faculty of the Hopkins Neuroscience Department, 2005 Lowest row (left to right): Dwight Bergles, Gabriele Ronnett, Rudiger von der Heydt, Solomon Snyder, Richard Huganir, Susanne Boeke (administrator), Shanthini Sockana- than. Middle row (left to right): Stephen Hsiao, Jay Baraban, Ernst Niebur, Alex Ko- lodkin, Min Li, Seth Blackshaw, C. Edward Connor, Jonathan Pevsner. Upper row (left to right): Mark Molliver, Alfredo Kirkwood, King Wai-Yau, Nicholas Marsh-Armstrong, Xinzhong Dong, David Linden, David Ginty.

David Robinson pioneered in elucidating the vestibulo- vard/Massachusetts General Hospital, Columbia, the ocular reflex. The reflex maintains constancy of images University of at San Francisco, and Johns on the fovea of the retina as the head rotates. It does Hopkins as sites for a neuroscience enterprise. Dan Na- this by causing the eyes to rotate at the same speed thans, representing the already existing HHMI Molecular as the head but in an opposite direction. In one classic Biology Institute, and myself, along with other faculty study, Robinson showed that this presumably ‘‘hard- advisors, in 1986 recruited the first HHMI neuroscience wired’’ reflex is modulated by experience, with the cere- faculty, Richard Huganir, King-Wai Yau, and Gary Yellen, bellum critical for such modulation (Robinson, 1976). He into the Neuroscience Department component of the also showed that the detects and repairs HHMI neuroscience program. Randall Reed and Jeremy dysmetria, a midjudgement of distances in motor Nathans also joined the HHMI Neuroscience Institute movements. with primary appointments in Molecular Biology and Ge- Murray Sachs, presently Director of the Department of netics and secondary appointments in Neuroscience. Biomedical Engineering, and Eric Young pioneered in Subsequently, Yellen left Hopkins for Harvard. After defining the code for detecting speech sounds, espe- HHMI modified its procedure for developing new faculty, cially vowels. They showed that vowel perception is en- adopting a national competition approach, David Ginty coded by increased firing rates but that there is a dy- and Alex Kolodkin, existing neuroscience faculty, were namic range wherein the discharge rate of auditory appointed as HHMI members. nerve fibers is capped (Sachs and Young, 1980). Besides constructing new space for its own laborato- ries, HHMI provided a long-term loan of another Department of Neuroscience research floor to the medical school. Thus, at the Although our department was founded in 1980, we had same time that the HHMI Neuroscience Institute was no independent laboratory space until 1983, when our launched, a group of neurophysiologists left the Physiol- first recruits, Richard Mains and Elizabeth Eipper, joined ogy Department to join the Neuroscience Department in Kuhar, Coyle, and myself as full professors (Figure 2). the HHMI-donated space. The group, designated the Mains and Eipper had done postdoctoral work with Ed- Bard Laboratories of Neurophysiology and led by Ver- ward Herbert at the University of Oregon, where they non Mountcastle, included Kenneth Johnson, Gian Pog- discovered pro-opiomelanocortin, the protein precursor gio, and Steven Hsiao. At the same time, Mark Molliver of ACTH and b-endorphin. They then pioneered in the and Reinhard Grzanna, neuroanatomists in the Cell Biol- biochemistry of processing (Eipper et al., ogy/Anatomy Department, joined the Neuroscience De- 1992). I felt it important to begin with senior faculty partment in the space provided by HHMI. Subsequently, who could share some of the administrative responsibil- more basic-science laboratory space was constructed, ities of a new department. Mains and Eipper rose to the enabling us to recruit additional faculty, including David challenge, launching our graduate program. Besides de- Linden, Paul Worley, Gabriele Ronnett, and Fabio Rupp veloping a curriculum and recruiting students, they set (Rupp subsequently left Hopkins to join a biotech com- up a departmental seminar series and a substantial pany in California). number of graduate courses. When Kuhar left Hopkins In the mid-1990s, a Mind/Brain Institute was estab- in 1985, we recruited Jay Baraban, a Yale M.D./Ph.D., lished on the College of Arts and Sciences campus of who trained with George Aghajanian and, following psy- Johns Hopkins, and the neurophysiology group moved chiatry residency at Columbia, did postdoctoral re- to this location. The additional space enabled the search with me. Mind/Brain Institute to recruit new faculty, such as Stew- The next major impetus for departmental expansion art Hendry, Rudiger von der Heydt, Edward Connor, came with the launching by the Howard Hughes Medical Ernst Niebur, and Alfredo Kirkwood, all with primary ap- Institute (HHMI) of a neuroscience initiative. In those pointments in the Neuroscience Department. The space days, HHMI operated by setting up ‘‘institutes’’ in vari- freed by the departure of neurophysiologists from the ous disciplines at selected medical schools. The direc- medical campus permitted further faculty recruitment tors of such institutes recruited whoever they wished with a focus in developmental neurobiology—David (with approval of HHMI). In the mid-1980s, HHMI de- Ginty, Alex Kolodkin, and Anirvan Ghosh. In 2000, cided to explore the neurosciences and ‘‘tapped’’ Har- Drs. Mains and Eipper left Hopkins to launch a new Neuron 206

Department of Neuroscience at the University of Con- and . Here again, conventional protein necticut and were replaced by Dwight Bergles and purification was key. The only way to learn much about Shanthini Sockanathan. In 2003, Min Li transferred his an evanescent molecule such as would be primary appointment from Physiology to Neuroscience. to find the that makes it, but efforts in numerous When Anirvan Ghosh departed in 2004 for an endowed laboratories had failed because NO synthase appeared professorship at UCSD, we recruited Xinzhong Dong, to be extraordinarily labile. Knowing that was whose postdoctoral research at Caltech with David An- somehow involved in NO formation, my M.D./Ph.D. stu- derson uncovered the novel Mrg family of pain-mediat- dent David Bredt added calmodulin to crude enzyme ing channels. Seth Blackshaw recently joined our preparations, stabilizing the protein, facilitating its puri- faculty elucidating differential gene expression in devel- fication and cloning and explaining how neuronal depo- oping cell types in the retina and hypothalamus. Follow- larization can activate NO formation by causing calcium ing his doctoral research in my lab, he worked with Con- to enter cells and bind to calmodulin (Bredt et al., 1991). stance Cepko at Harvard on retinal cell lineage. Primary Soon, it was possible to establish that NO is a major neu- faculty housed in the Kennedy Krieger Institute on the rotransmitter of the as well medical campus include Catherine Thompson, Jona- as regulating sexual and aggressive behavior in the than Pevsner, and Nicholas Marsh-Armstrong. brain (Nelson et al., 1995). Since neurotransmitters Typically, departmental development in medical come in chemical classes, we looked for other gaseous schools involves a dowry for a new chair to fill the de- transmitter candidates and obtained compelling evi- partment with faculty who then age so that the depart- dence that carbon monoxide, derived from by ment falters until a new chair is recruited. Various events, a neuronal form of heme oxygenase, is a coneurotrans- many fortuitous, enabled us to avoid this dilemma. The mitter with NO mediating nonadrenergic-noncholinergic chronology described above reflects a means whereby in the autonomic nervous system. over 25 years our department was periodically renewed Our interest in atypical transmitters led to studies with an influx of new, young faculty affording fresh per- showing that the unnatural D-isomer of is a neuro- spectives. modulator generated by and serving as an endoge- Another unique feature of our department, at least nous ligand for the ‘‘glycine’’ site of NMDA receptors, among basic-science departments at Hopkins, is our re- hence acting as a coagonist with glutamate at these re- cruitment of secondary faculty reflecting an abundance ceptors in the brain. Elucidation of D-serine as a trans- of neuroscience research throughout the university. mitter led to further collaborations with Huganir. We Presently, we have 78 secondary and joint appoint- showed that serine racemase, the enzyme that we dis- ments, individuals who are not merely window dressing covered to generate D-serine from L-serine, binds to but make major contributions to department teaching GRIP, a PDZ domain-containing protein discovered by and research. Huganir in collaboration with Paul Worley, which in- There are too many current faculty to describe all their teracts with AMPA-glutamate receptors. Synaptically research. Here I will focus on a limited number of exam- released glutamate activates AMPA receptors on glia ples that highlight some of the questions being investi- causing GRIP to bind to serine racemase and massively gated as well as showcasing collaborative interactions. activate its formation of D-serine (Kim et al., 2005). Huganir has been a world leader in the regulation of Signaling neurotransmitter receptor regulation by phosphoryla- Signaling at the level of neurotransmitters and proteins tion as well as by binding to receptor-interacting pro- regulating receptor responses as well as intracellular teins such as GRIP. In his early studies with Paul Green- second messengers has constituted a major theme in gard, Huganir showed how phosphorylation regulates the department. In my own laboratory, the reversible li- desensitization of nicotinic receptors, gand-binding technology that permitted the identifica- with both serine and phosphorylation playing tion of neurotransmitter receptors was extended to sec- major roles (Huganir et al., 1986). He extended this ond messengers. Thus, Jay Baraban and Paul Worley, work to numerous receptors, including those for GABA then fellows in my lab, used binding techniques to iden- as well as NMDA and AMPA forms of glutamate recep- tify receptors for the second 1,4,5- tors. He then addressed the role of receptor phosphory- trisphosphate (IP3). At that time, the mid 1980s, we labo- lation in and memory. Abundant work riously solubilized, then purified IP3 receptor protein. favored a role for phosphorylation of synaptic proteins in Molecular cloning of proteins as large as IP3 receptors, synaptic plasticity, but there was no direct evidence. In about 300 kDa, was in its infancy. To learn how the IP3 a tour-de-force, Huganir generated mice with knockin receptor might influence calcium conductance, we col- mutations in selected phosphorylation sites of the laborated with Huganir, incorporating the receptors GluR1 subunit of AMPA receptors (Lee et al., 2003). into vesicles labeled with radioactive calcium and The mutant mice showed defects in long-term depres- showed that IP3 released calcium, establishing that sion (LTD) and long-term potentiation (LTP) as well as the IP3 receptor protein contained the calcium ion chan- memory defects in spatial learning tasks. He also has nel as well as the IP3 recognition site (Ferris et al., 1989). identified numerous proteins that regulate synaptic plas- These studies would have been impossible were it not ticity (Ye et al., 2000; Dong et al., 1997). for Huganir’s doctoral research with Ephraim Racker es- David Linden, a cellular electrophysiologist, has col- tablishing that the nicotinic pro- laborated extensively with Huganir and Worley in clarify- tein contains the relevant sodium channel. ing molecular bases of LTD and LTP. Linden pioneered We became interested in novel neurotransmitters, es- models of cerebellar LTD in culture systems which re- pecially gaseous molecules such as nitric oxide (NO) place stimulation of nerve fibers with bath application Historical Perspective 207

of glutamate. He discovered novel modes of cerebellar his investigations to a variety of diseases, in the process plasticity, such as synaptically driven changes in the in- discovering novel regulatory mechanisms. For instance, trinsic excitability of deep nuclei as well as LTD of the he identified the gene underlying the vitelliform type climbing-fiber (Hansel and Linden, 2000). In of macular dystrophy and showed that it defines a new collaboration with Huganir, Linden showed that phos- family of chloride ion channels, a study conducted in phorylation of the GluR2 type of AMPA receptor is collaboration with King-Wai Yau (Sun et al., 2002). A required for cerebellar LTD (Chung et al., 2003). Thus, long-term goal has been to find causes of macular LTD is absent from cultured cerebellar Purkinje cells of degeneration, a common form of blindness. Stargardt mutant mice lacking GluR2 receptors and can be res- macular dystrophy is a relatively rare genetic form of cued by transfection with wild-type. Huganir had this condition for which Nathans characterized a photo- showed that protein kinase C phosphorylation of ser- receptor cell-specific mutation in the ATP-binding trans- ine-880 in the carboxyl-terminal PDZ ligand of GluR2 is porter gene (Sun et al., 2000). critical for plasticity of the receptors. Linden discovered King Wai-Yau has long been a pioneer in phototrans- that transfecting the GluR2 null Purkinje cells with a mu- duction. He discovered the critical role of cyclic GMP in tant that prevents PKC phosphorylation at serine-880 phototransduction and then showed how cyclic GMP fails to rescue LTD. and calcium work together (Haynes et al., 1986; Naka- Following postdoctoral training in my laboratory tani and Yau, 1988). Light produces a hyperpolarizing re- where he identified IP3 receptors, Paul Worley teamed sponse in rods by triggering a decrease in cyclic GMP up with Jay Baraban to identify a series of immediate and thus closure of cyclic GMP-activated channels. early genes that are upregulated by selective neuronal The closing of these channels leads to decreased cal- activation. Worley then spent three years in the labora- cium levels in the rod outer segment, activating nega- tory of Dan Nathans obtaining molecular biological ex- tive-feedback pathways to bring about light adaptation. pertise that enabled him to characterize these genes, Recently, Yau discovered a novel population of photore- many of which have emerged as major regulators of syn- ceptors that are neither rods nor cones and which en- aptic plasticity. One of the most important, identified in able light to synchronize circadian rhythms even in blind collaboration with Huganir, is Homer, first described as animals and people. In collaboration with David Berson an immediate early gene whose protein product binds at Brown University, he identified a small population of selectively to metabotropic glutamate receptors (Brake- retinal ganglion cells that express a novel pigment, mel- man et al., 1997). In collaboration with David Linden, anopsin (Hattar et al., 2002). The -containing Worley showed that Homer binds within its target pro- ganglion cells project to the of teins to a novel -rich motif, the ‘‘Homer ligand,’’ the hypothalamus, the central circadian pacemaker of enabling a Homer dimer to bring IP3 receptors and the the brain, as well as to brain nuclei that regulate the pu- metabotropic glutamate receptors in proximity. This pillary light reflexes that are maintained in blind animals. process permits metabotropic glutamate neurotrans- Mice with genetic deletion of melanopsin display impair- mission to influence IP3 release of calcium (Tu et al., ments in light entrainment of circadian rhythms. 1998). He subsequently showed that Homer can regu- Yau also has been a leader in olfactory transduction. late calcium entry into cells as it cross links IP3 recep- About 12 years ago, he identified an unusual depolariz- tors and TRP calcium channels in the plasma mem- ing calcium-activated chloride current that is crucial for brane, explaining how IP3 receptors regulate calcium olfactory transduction. Recently, he discovered a dra- entry (Yuan et al., 2003). matic difference between signaling in olfaction and vision (Bhandawat et al., 2005). It has long been as- Sensory Transduction sumed that a single G protein-coupled receptor acti- Hopkins has a long tradition of sensory research. vates vast numbers of G proteins, a phenomenon well Mountcastle’s pioneering work on the columnar organi- established for rod phototransduction. In contrast, fol- zation of the brain was based on investigations of tactile lowing binding of odorants, their receptors have a very stimuli, a body of work carried forward by the late Ken- low probability of activating even a single downstream neth Johnson and by Steve Hsiao. Hubel and Weisel G molecule, because odorants remain in contact with re- brought the columnar concept into studies of photo- ceptors for less than a millisecond. It appears likely that transduction. Auditory neurophysiology has long been the model for olfaction is the norm for G protein signaling a strength, as described above in the research of Murray and that the amplification scheme for phototransduction Sachs and Eric Young. In recent years, molecular inves- is an exception. tigations of diverse , including vision, smell, and Randy Reed has also pioneered in molecular ap- pain perception, have been areas of intense activity. proaches to olfaction. He cloned a unique odorant-bind- Jeremy Nathans obtained his M.D./Ph.D. at Stanford. ing protein as well as olfactory-selective G proteins, ad- Working independently in the laboratory of David Hog- enylyl cyclase and cAMP-regulated ion channels. He has ness, he cloned the gene for rhodopsin and used this elucidated promoters that determine the localization of as a template to identify the genes for color vision. He odorant receptors as well as the restrictive expression then obtained blood samples of individuals suffering in individual olfactory neurons of only single-odorant from diverse forms of color blindness and elucidated receptors (Lewcock and Reed, 2004). the molecular basis for the principal types of color blind- Michael Caterina is a Hopkins-trained M.D./Ph.D. who ness. This body of work, published in two lead articles in did his thesis work with Peter Devreotes elucidating sig- Science, revolutionized color-vision research (Nathans nal transduction by cyclic AMP in regulating aggregation et al., 1986a, 1986b). Nathans has continued to clarify of the amoebae comprising slime molds. He then joined molecular bases of phototransduction and extended David Julius at the University of California at San Neuron 208

Francisco, where he successfully cloned the receptor University of California at Berkeley, where he discovered for the active ingredient in hot peppers, capsaicin the semaphorins, the first family of proteins that mediate (Caterina et al., 1997). This receptor, also called the va- axonal pathfinding by repelling other neurons. Together nilloid receptor (TRPV1), is a member of the TRP family with Ginty, Kolodkin identified the first cell-surface sem- of plasma-membrane calcium channels discovered by aphorin receptor, neuropilin1 (Kolodkin et al., 1997). Ko- Craig Montell, a Hopkins Professor of Biochemistry lodkin then uncovered a novel, enzymatic regulation of with a secondary appointment in Neuroscience (Montell neuronal repulsion by isolating MICAL, a large cytosolic et al., 2002). At Hopkins, as a faculty member in Biolog- axonal protein that binds to plexin-A, one of the sema- ical Chemistry with a secondary appointment in Neuro- phorin receptors, and is required for the ability of sema- science, Caterina has greatly extended his initial phorin 1A to repel (Terman et al., 2002). MICAL findings. Mice with targeted deletion of TRPV1 demon- has a flavoprotein monooxygenase domain, whose strate major impairments in pain perception, while dele- integrity is required for axonal repulsion. Thus, an enzy- tion of a heat-selective channel alters heat perception matic oxidoreductase activity appears critical for repul- (Lee et al., 2005). Caterina cloned a family of related sive neuronal guidance, which opens the way to enzyme ion channels, some of which respond to heat but not inhibitors as therapeutic agents. to protons or capsaicin. Remarkably, there is a ‘‘cold’’ David Ginty has been a leader in characterizing signal- receptor in the family that is activated by menthol and ing by nerve (NGF) and related neurotro- other ‘‘cold-eliciting’’ substances. phic growth factors. He was the first to show that vesic- Sensory perception is a major focus of the systems ular trafficking of the complex of NGF and its receptor neuroscientists in the Mind/Brain Institute. The scientific TrkA is responsible for retrograde NGF signaling from lineage of the group goes back to the approach devel- distal axons to neuronal cell bodies (Riccio et al., 1997; oped by Vernon Mountcastle of correlating behavior of Ye et al., 2003). He observed that this retrograde sig- awake, performing monkeys with the activity of individ- naling requires CREB-dependent gene expression for ual neurons in the cerebral cortex. Mountcastle trained NGF-determined growth and neuronal survival the late Kenneth Johnson, former Director of the Mind/ (Lonze et al., 2002). He recently illuminated how NGF Brain Institute, who in turn trained and collaborated interacts with the related NT-3 (Kuruvilla with Steven Hsiao. Hsiao and Johnson continued the et al., 2004). NT-3 released from blood vessels enhances strategy initiated by Mountcastle of employing tactile the growth of axons as they move toward their ultimate sensation as an entre´ e to how the cerebral cortex inte- target field. In order for axons to reach their targets, they grates sensory information. One focus has been an elu- must ‘‘decathect’’ NT-3. This is accomplished by NGF cidation of modality-specific attention, which allows us augmenting the expression of the auxiliary NGF receptor to disregard sensory information when it is irrelevant p75, which causes TrkA to become less responsive to (e.g., the constant pressure of clothing on our bodies) NT-3. or highlight it when it is important (e.g., the spatial pat- Another relationship of vasculature and tern of pressure on the fingers when reading Braille). is evident in a Ginty-Kolodkin collaboration based on the Their research suggests that attention to touch depends finding that neuropilin1 is also a receptor for vascu- on increased synchronization between neurons in pri- lar endothelial growth factor (VEGF). Utilizing genetic mary somatosensory cortex (Steinmetz et al., 2000), as knockin mice, the team showed that while sema- predicted in theories elaborated by Ernst Niebur (Niebur phorin-neuropilin1 signaling mediates axon guidance, et al., 2002). Other work focuses on higher-level somato- development of the vasculature depends on VEGF-neu- sensory cortex and its role in three-dimensional-object ropilin1 signaling, and formation of the heart requires perception with the hand (Fitzgerald et al., 2004). both types of signaling (Gu et al., 2003). Interestingly, Rudiger von der Heydt and Ed Connor (another stu- semaphorin signaling is also critical for vascular devel- dent of Johnson’s) study object perception in the visual opment, but in a neuropilin1-independent manner in- system. Von der Heydt has shown how complex Gestalt volving the divergent semaphorin receptor plexin D1 principles for inferring objects from multiple two- and (Gu et al., 2005). three-dimensional-contour cues are embodied by the activity of neurons in primary and secondary visual cor- Clinically Relevant Neuroscience tex (Peterhans and von der Heydt, 1991; Qiu and von der Neuroscience research has prospered in clinical de- Heydt, 2005). Connor focuses on higher-level visual cor- partments at Hopkins, whose researchers possess sec- tex, where objects are represented as configurations of ondary appointments in our department. Fundamental parts, by populations of neurons encoding the local ge- molecular neuroscience with clinical relevance is exem- ometry and relative positions of contour and surface plified in the work of Ted Dawson, Valina Dawson, and fragments (Brincat and Connor, 2004; Pasupathy and Christopher Ross. Ted Dawson obtained his neurology Connor, 2002). training at the University of Pennsylvania, where Valina Dawson was a postdoctoral researcher. They subse- Developmental Neurobiology quently did advanced postdoctoral work in my own lab- Our department’s efforts in molecular approaches to de- oratory, following which they joined the Department of velopment have featured close interactions between Neurology with secondary appointments in Neurosci- David Ginty, Alex Kolodkin, and, till he moved recently ence. The Dawsons worked with me soon after the clon- to the University of California at San Diego, Anirvan ing of neuronal NO synthase. They discovered that NO Ghosh. Both Ginty and Ghosh were postdoctoral fellows mediates neurotoxicity caused by glutamate-NMDA re- with Michael Greenberg at Harvard. Kolodkin obtained ceptor stimulation. In their own laboratory, in collabora- his postdoctoral training with Corey Goodman at the tion with our group, they showed that this neurotoxicity Historical Perspective 209

is associated with overactivation of poly(ADP-ribose) facilitated recruitment of a cadre of young, dynamic fac- polymerase1 (PARP1) (Eliasson et al., 1997). PARP1 is ulty as well as integration of neuroscience research a DNA-repair enzyme which employs NAD as a sub- throughout the university. Our departmentally based strate. Overstimulation of PARP following neurotoxic in- graduate program has generated talented investigators sults depletes NAD and then ATP so that cells die of en- who now populate universities nationwide. Intimate col- ergy deficit. They showed that PARP1-knockout mice legial relationships have spawned multiple collabora- manifest up to an 80% protection from damage. tions among basic and clinical neuroscientists leading They subsequently elucidated downstream aspects of to numerous scientific advances. this pathway, identifying a novel caspase-independent pathway of programmed cell death involving apopto- Acknowledgments sis-inducing factor (AIF) acting downstream of NO and PARP1 (Yu et al., 2002). Supported by USPHS grants DA000266 and MH18501 and Research The Dawsons have also clarified the pathophysiology Award DA00074. of Parkinson’s disease. Mutations in parkin, a ubiquitin- 3-ligase, cause a form of recessive Parkinson’s disease. References They discovered that S-nitrosylation of parkin impairs its function, which provides a mechanism whereby cyto- Abel, J.J. (1926). Crystalline insulin. Proc. Natl. Acad. Sci. USA 12, toxic insults, via NO, may lead to the common sporadic 132–136. form of Parkinson’s disease (Chung et al., 2004). Abel, J.J., and Crawford, A. (1897). On the blood-pressure raising Christopher Ross obtained his M.D./Ph.D. at Cornell constituent of the suprarenal capsule. Trans. Assoc. Am. Phys. 12, 461. with the late Donald Reis. After a Hopkins psychiatry residency and further postdoctoral time in my own lab- Bae, B.I., Xu, H., Igarashi, S., Fujimuro, M., Agrawal, N., Taya, Y., Hayward, S.D., Moran, T.H., Montell, C., Ross, C.A., et al. (2005). oratory, he joined the Psychiatry Department with sec- p53 mediates cellular dysfunction and behavioral abnormalities in ondary appointments in Neuroscience and Neurology. Huntington’s disease. Neuron 47, 29–41. He has focused on molecular features of neurodegener- Bhandawat, V., Reisert, J., and Yau, K.W. (2005). Elementary re- ative diseases, especially Huntington’s disease. For in- sponse of olfactory receptor neurons to odorants. Science 308, stance, in collaboration with the Dawsons, Ross showed 1931–1934. that mutant huntingtin binds the transcriptional co- Bodian, D. (1955). Emerging concept of poliomyelitis infection. Sci- activator CREB-binding protein, CBP (Nucifora et al., ence 122, 105–108. 2001). In Huntington’s disease postmortem brain (as Bodian, D. (1966). Electron microscopy: Two major synaptic types well as Huntington’s disease transgenic mice and cell on spinal motorneurons. Science 151, 1093–1094. culture models), CBP was depleted from its nuclear Brakeman, P.R., Lanahan, A.A., O’Brien, R., Roche, K., Barnes, localization and appeared instead in polyglutamine C.A., Huganir, R.L., and Worley, P.F. (1997). Homer: a protein that aggregates. Overexpression of CBP rescued polyglut- selectively binds metabotropic glutamate receptors. Nature 386, -induced neuronal . Thus, polyglutamines 284–288. in Huntington’s disease and related disorders damage Bredt, D.S., Hwang, P.M., Glatt, C.E., Lowenstein, C., Reed, R.R., cells in part by interfering with CBP-regulated gene tran- and Snyder, S.H. (1991). Cloned and expressed nitric oxide syn- thase structurally resembles cytochrome P-450 reductase. Nature scription. In collaboration with the Dawsons, Ross has 351, 714–718. also studied Parkinson’s disease. In one study, they Brincat, S.L., and Connor, C.E. (2004). Underlying principles of vi- showed that parkin ubiquitinates synphilin-1, a protein sual shape selectivity in posterior inferotemporal cortex. Nat. Neu- identified by Ross’ group as associated with a-synuclein rosci. 7, 880–886. and present in the Lewy bodies of Parkinson’s disease Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Lev- brain. Whereas ubiquitination normally leads to protein ine, J.D., and Julius, D. (1997). The capsaicin receptor: a heat-acti- degradation, the Dawson-Ross team found that the vated in the pain pathway. Nature 389, 816–824. ubiquitination of synphilin-1 occurs in a nonclassical, Chung, K.K., Zhang, Y., Lim, K.L., Tanaka, Y., Huang, H., Gao, J., proteasome-independent fashion, likely contributing to Ross, C.A., Dawson, V.L., and Dawson, T.M. (2001). Parkin ubiqui- Lewy body formation (Chung et al., 2001). tinates the alpha-synuclein-interacting protein, synphilin-1: impli- Recently, Ross has collaborated with our own labora- cations for Lewy-body formation in Parkinson disease. Nat. Med. tory in studies with Akira Sawa and Byoung Il-Bae show- 7, 1144–1150. ing that the tumor suppressor p53 mediates cellular dys- Chung, H.J., Steinberg, J.P., Huganir, R.L., and Linden, D.J. (2003). function and behavioral abnormalities in Huntington’s Requirement of AMPA receptor GluR2 phosphorylation for cerebel- lar long-term depression. Science 300, 1751–1755. disease (Bae et al., 2005). 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