Northwestern University Feinberg School of Medicine
Department of Pharmacology
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Neuropharmacology

Neuropharmacology is the study of how drugs affect the molecular, cellular or behavioral functions of the central and peripheral nervous system. Faculty in our department use modern tools of neuroscience to investigate fundamental brain processes implicated in several neurological disorders — including epilepsy, addiction, ataxia, dystonia, intellectual disability, Parkinson's disease, neuropathic pain and Alzheimer's disease — then translate this knowledge into discovery and development of novel therapeutic strategies.

Our Work

Investigating Cellular and Physiological Properties of Nicotine

Investigating Cellular and Physiological Properties of Nicotine

Ryan Drenan, PhD, associate professor of Pharmacology, investigates the critical cellular and physiological properties associated with nicotine.

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Examining How Genetics Can Influence Epilepsy in Children

Jennifer Kearney, PhD, associate professor of Pharmacology, works in conjunction with the clinicians at Northwestern Memorial Hospital and the Ann and Robert H. Lurie Children’s Hospital of Chicago to learn how an individual’s genetic background influences epilepsy.

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How Genetics Can Influence Epilepsy in Children
Neuronal Signaling at a Molecular and Cellular Level

Neuronal Signaling at a Molecular and Cellular Level

Geoff Swanson, PhD, professor of Pharmacology, studies how brain cells communicate with each other during normal circumstances, during memory processes and how the processes go wrong in disease.

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Developing Mechanistic Based Therapeutic Opportunities for Parkinson’s Disease

Loukia Parisiadou, PhD, assistant professor of Pharmacology, uses a multidisciplinary approach spanning cellular, molecular, network and behavioral levels to understand the molecular basis of Parkinson’s disease.

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Therapeutic Opportunities for Parkinsons Disease

Neuropharmacology Research Labs

 Gemma Carvill Lab

Genetic causes and pathogenic mechanism that underlie epilepsy

Research Description

The primary goal of our research is to use gene discovery and molecular biology approaches to identify new treatments for epilepsy. We aim to 1) identify the genetic causes of epilepsy, 2) use stem cell models to understand how genetic mutations can cause epilepsy, 3) develop and test new therapeutics for this condition. Our work is based on the promise of precision medicine where knowledge of an individual’s genetic makeup shapes a personalized approach to care and management of epilepsy.

Current Projects

  • Next generation sequencing in patients with epilepsy
  • Alternative exon usage during neuronal development
  • Identify the regulatory elements that control expression of known epilepsy genes
  • Stem cell genetic models for studying the epigenetic basis of epilepsy

For more information, see Dr. Carvill's faculty profile or the Carvill Lab Website.

Publications

Please see Dr. Caraveo Piso's publications on PubMed.

Contact Information

Gemma L. Carvill, PhD

 Paul DeCaen Lab

Studying ion channel relevance in cell biology and disease progression

Research Description

We study the biophysics, pharmacology and physiology of ion channels. Currently, we are focused on two divergent groups: voltage gated sodium channels (Nav) and Polycystin channels (also called Polycystic Kidney Disease Proteins, PKDs). Aside from these foci, we actively explore novel ion channels found in prokaryotic and eukaryotic cells with the goal of understanding their function in cell physiology.

Current Projects

Voltage Gated Sodium Channels

Navs conduct sodium ions into excitable cells like muscle and neurons, causing the cell membrane to depolarize on the microsecond time scale, a process essential for rapid communication in multicellular organisms. Potentially fatal conditions such as forms of epilepsy and cardiac arrhythmias arise when Navs are mutated.

With our collaborators, we continue to examine key questions:

  • How do these transmembrane proteins sense electrical potential and change from nonconductive to conductive states?
  • How do these transmembrane proteins select for sodium ions and not allow passage of the other ions present?     
  • What are the mechanisms of action of clinically relevant drugs (e.g. Valproate and Lamotrigine) and where are their receptor sites?

Polycystin Channels and Primary Cilia

Mutations in PKD1 and PKD2 are associated with Autosomal Dominant Kidney Disease (ADPKD). ADPKD is one of the most common monogenetic diseases in mankind, where progressive cyst formation results in kidney failure. Several members of the polycystins (PKD1, PKD1-L1, PKD2 and PKD2-L1) have been found in the primary cilia from cells of various tissues besides the kidney. The primary cilium is a solitary, small (5-15 mM in length) protuberance from the apical side of polarized cells.

With help from our collaborators, our research is directed to answer key questions:

  • How do ADPKD mutations alter PKD2 function? Do some mutations ‘turned on’ while others ‘turn off ’ the PKD2 channel?
  • How does PKD1/2 channel dysfunction result in cyst formation? Or conversely, what normal function do they serve for the primary cilium and how do PKDs maintain cell polarity?
  • What are the receptor sites within PKD2s that can modulation its ion channel function and are they drug-able?

For lab information and more, see Dr. DeCaen's faculty profile and lab website.

Publications

See Dr. DeCaen's publications on PubMed.

Contact

Contact Dr. DeCaen at 312-503-5930.

Lab Staff

Postdoctoral Fellow

Leo C.T. Ng

Lab Manager

Thuy Vien

 Ryan Drenan Lab

Studying the neuropharmacology and neurobiology of cholinergic neurotransmission in the brain

Research Description

Our lab is investigating the role of α4 and α6 nAChRs in the response to nicotine using cellular and systems neuroscience approaches. Most nAChR mouse genetics involves KO or transgenic animals where the mutation in question has been present from early embryogenesis, raising the possibility for developmental artifacts. We have improved upon this approach and eliminated the possibility for developmental artifacts by devising a method to knockout nAChR subunits in specific neuron types and in adult animals. By delivering Cre-expressing viral vectors to specific brain areas in mice with loxP sites flanking, for example, the α4 nAChR gene, we have achieved brain-region specific nAChR gene silencing in the adult animal. By combining the Cre virus/loxP technique with other mouse strains, we are achieving unprecedented precision with regard to studying the function of specific nAChRs in cell-types in the DA reward system.

We are also pursuing work aimed at identifying the adaptive cellular changes that result from exposure to nicotine. To accomplish this, we utilize two complementary approaches associated with chronic nicotine exposure to animals: 1) brain slice patch clamp electrophysiology to study changes to nAChR pharmacology and glutamatergic transmission and 2) biolistic (gene-gun mediated) labeling of individual neurons to identify and quantify changes to glutamatergic synapses. In both cases, we also use specific mouse lines to assign cellular changes to specific nAChR subtypes and their host neuron types.

Addiction to drugs, such as nicotine, is dependent on the net motivational affect of the drug; both the positive (reward-causing) and negative (aversion-causing) effects of the drug must be considered. Nicotine dependence in humans persists mainly due to the negative affective state associated with nicotine withdrawal. Thus, a better understanding of the cellular mechanisms underlying nicotine withdrawal could lead to novel approaches to fostering nicotine cessation. An area of the brain known as the medial habenula (MHb), which expresses tremendously high amounts of nAChRs, has been recently shown to be essential for nicotine withdrawal. Unfortunately, the neuron types and the nAChR pharmacology in the MHb remain unclear.

To address this critical gap in knowledge, we created a suite of nAChR-GFP knock-in mouse strains for 6 different nAChR subunits expressed in MHb. Using these mice, we mapped nAChR expression in the MHb. To our surprise, we identified several nAChR subunits with highly specific expression only in certain cell types in MHb. We further studied these cell types using brain slice patch clamp electrophysiology and identified several physiologically distinct neuron types, along with pharmacologically distinct nAChRs. By chronically treating mice with nicotine, we have further identified highly specific changes to neuronal excitability and nAChR pharmacology within specific subregions of MHb. These cellular changes could be the key adaptive responses that explain the
generation of nicotine withdrawal signs/symptoms.

For more information, please see Dr. Drenan's faculty profile, or visit the Drenan Laboratory site.

Publications

See Dr. Drenan's publications on PubMed.

Contact

Contact Dr. Drenan at 312-503-4956.

Lab Staff

Postdoctoral Fellows

Xiaotao Jin, Can PengYong Wang, Yijin Yan

Technical Staff

Veronica Kim

Visiting Scholar

Matthew Arvin

 Al George Lab

Investigating the structure, function, pharmacology and molecular genetics of ion channels and channelopathies

George Lab

Research Description

Ion channels are ubiquitous membrane proteins that serve a variety of important physiological functions, provide targets for many types of pharmacological agents and are encoded by genes that can be the basis for inherited diseases affecting the heart, skeletal muscle and nervous system.

Dr. George's research program is focused on the structure, function, pharmacology and molecular genetics of ion channels. He is an internationally recognized leader in the field of channelopathies based on his important discoveries on inherited muscle disorders (periodic paralysis, myotonia), inherited cardiac arrhythmias (congenital long-QT syndrome) and genetic epilepsies. Dr. George’s laboratory was first to determine the functional consequences of a human cardiac sodium channel mutation associated with an inherited cardiac arrhythmia. His group has elucidated the functional and molecular consequences of several brain sodium channel mutations that cause various familial epilepsies and an inherited form of migraine. These finding have motivated pharmacological studies designed to find compounds that suppress aberrant functional behaviors caused by mutations.

Recent Findings

  • Discovery of novel, de novo mutations in human calmodulin genes responsible for early onset, life threatening cardiac arrhythmias in infants and elucidation of the biochemical and physiological consequences of the mutations.
  • Demonstration that a novel sodium channel blocker capable of preferential inhibition of persistent sodium current has potent antiepileptic effects.
  • Elucidation of the biophysical mechanism responsible for G-protein activation of a human voltage-gated sodium channel (NaV1.9) involved in pain perception.

Current Projects

  • Investigating the functional and physiological consequences of human voltage-gated sodium channel mutations responsible for either congenital cardiac arrhythmias or epilepsy.
  • Evaluating the efficacy and pharmacology of novel sodium channel blockers in mouse models of human genetic epilepsies.
  • Implementing high throughput technologies for studying genetic variability in drug metabolism.
  • Implementing automated electrophysiology as a screening platform for ion channels.

For lab information and more, see Dr. George’s faculty profile.

Publications

See Dr. George's publications on PubMed.

Contact

Contact Dr. George at 312-503-4892.

Lab Staff

Research Faculty

Lynn DoglioVladimir Jovasevic, Andrew Mazar, Franck PotetMegan Roy-PuckelwartzChristopher Thompson, Carlos Vanoye

Senior Researchers

Reshma Desai, Jean-Marc DekeyserPaula FriedmanChristine Simmons

Lab Manager

Tatiana Abramova

Postdoctoral Fellows

Thomas HolmDina Simkin

Medical Resident

Tracy Gertler

Graduate Students

Surobhi Ganguly, Grace Kelly, Lisa Wren

Technical Staff

Shannon Gallagher

 Jennifer Kearney Lab

Investigating the genetic basis of epilepsy

Research Description

My research program is focused on studying the genetic basis of epilepsy, a common neurological disorder that affects approximately 1% of the population. Epilepsy is thought to have a genetic basis in approximately two-thirds of patients, including a small fraction caused by single gene mutations. Many genes responsible for rare, monogenic epilepsy have been identified. The genes identified are components of neuronal signaling, including voltage-gated ion channels, neurotransmitter receptors, ion-channel associated proteins and synaptic proteins. We use mouse models with mutations in ion channel genes to understand the underlying molecular basis of epilepsy and to identify modifier genes that influence phenotype severity by modifying disease risk. Identifying genes that influence epilepsy risk improves our understanding of the underlying pathophysiology and suggests novel targets for therapeutic intervention.

For lab information and more, see Dr. Kearney's faculty profile.

Publications

See Dr. Kearney's publications on PubMed.

Contact

Contact Dr. Kearney at 312-503-4894.

Lab Staff

Research Faculty

Nicole Hawkins

Postdoctoral Fellows

Jeffrey Calhoun

Graduate Students

Erin Baker, Seok Kyu Kang

Technical Staff

Samantha DuarteManuel Jurado Jr, Tyler Thaxton, Nicole Zachwieja

Temporary Staff

Isaiah Eckart-Frank

 John Kessler Lab

Focusing on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system.

Research Description

The Kessler laboratory focuses on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system. A major interest of the laboratory has been the role of bone morphogenetic protein (BMP) signaling in both neurogenesis and gliogenesis and in regulating cell numbers in the developing nervous system.  Both multipotent neural stem cells and pluripotent embryonic stem cells are studied in the laboratory. Recent efforts have emphasized studies of human embryonic stem cells (hESC) and human induced pluripotent stem cells (hIPSC). The Kessler lab oversees the Northwestern University ESC and IPSC core and multiple collaborators use the facility. In addition to the studies of the basic biology of stem cells, the laboratory seeks to develop techniques for promoting neural repair in animal models of spinal cord injury and stroke. In particular, the lab is examining how stem cells and self-assembling peptide amphiphiles can be used together to accomplish neural repair. The lab is also using hIPSCs to model Alzheimer’s disease and other disorders. 

For more information see the faculty profile of John A Kessler, MD.

Publications

View Dr. Kessler's full list of publications in PubMed.

Contact

John Kessler, MD

 Tsutomu Kume Lab

The Kume Lab’s research interests focus on cardiovascular development, cardiovascular stem/progenitor cells and angiogenesis.

Research Description

Cardiovascular development is at the center of all the work that goes on in the Kume lab. The cardiovascular system is the first functional unit to form during embryonic development and is essential for the growth and nurturing of other developing organs. Failure to form the cardiovascular system often leads to embryonic lethality and inherited disorders of the cardiovascular system are quite common in humans. The causes and underlying developmental mechanisms of these disorders, however, are poorly understood. A particular emphasis in our laboratory has recently been the study of cardiovascular signaling pathways and transcriptional regulation in physiological and pathological settings using mice as animal models, as well as embryonic stem (ES) cells as an in vitro differentiation system. The ultimate goal of our research is to provide new insights into the mechanisms that lead to the development of therapeutic strategies designed to treat clinically relevant conditions of pathological neovascularization.

Publications

View Dr. Kume's publications on PubMed.

For more information, visit the faculty profile for Tsutomu Kume, PhD.

Contact Us

Contact Dr. Kume at 312-503-0623 or the Kume Lab at 312-503-3008.

Staff Listing

Austin Culver
MD Candidate
312-503-3008

Anees Fatima
Research Assistant Professor
312-503-0554

Christine Elizabeth Kamide
Senior Research Technologist
312-503-1446

Erin Lambers
PhD Candidate
312-503-5652

Ting Liu
Senior Research Technologist
312-503-3008

Jonathon Misch
Research Technologist
312-503-6153

 Daniela Maria Menichella Lab

Our laboratory investigates the molecular and physiological mechanisms underlying neuropathic pain in hereditary and acquired peripheral neuropathies with particular focus on Painful Diabetic Neuropathy (PDN).

Lab Description

PDN is a debilitating affliction present in 26% of diabetic patients with substantial impact on their quality of life. Despite this significant prevalence and impact, current therapies for PDN are only partially effective. Moreover, the molecular and electrophysiological mechanisms underlying neuropathic pain in diabetes are not well understood.

Neuropathic pain is caused by sustained excitability in sensory neurons which reduces the pain threshold, so that pain is produced in the absence of appropriate stimuli. Towards designing more effective therapeutics, our goal is to identify the molecular and physiological mechanisms that shape sustained excitability in sensory neurons responsible for the transition to neuropathic pain in peripheral neuropathies. More specifically we are investigating the role of molecules involved in inflammation such as chemokine and the potential role of microRNAs.

We take advantage of an integrated approach combining pain behavioral tests, electrophysiology studies including current clamp recordings, in vitro and in vivo calcium imaging studies, confocal studies with conditional and transgenic mouse genetic and chemo-genetic silencing of sensory neuron subtypes using mutated hM4D receptor (DREADD) receptors.

Publications

For more publication information see PubMed and for more information see the faculty profile of Daniela Maria Menichella, MD/PhD.

Contact

Daniela Maria Menichella, MD, PhD, at 312-503-3223

 Richard Miller Lab

Studying molecular aspects of nerve cell communication and neurodegenerative disease

Miller Lab Transgenic Reporter Mice

Colocalization of Nestin and GFAP in the DG of Nestin-EGFP Transgenic Reporter Mice

Research Description

The laboratory led by Richard Miller, PhD, is interested in studying molecular aspects of nerve cell communication. One of our major interests has been to understand the structure and function of calcium channels. The influx of Ca into neurons through these channels is important for many reasons, including the release of neurotransmitters. We have identified a family of molecules that act as Ca channels in neurons and other types of cells. Each of these molecules has slightly different properties that underly different neuronal functions. We have analysed the properties of these molecules by examining their electrophysiological properties following their expression in heterologous expression systems and imaging techniques. Furthermore, we have generated calcium channel knockout mice that have interesting properties such as altered pain thressholds, seizures and memory defecits. We have also been interested in how Ca channels can be regulated by the activation of Gprotein coupled receptors. We have been analyzing the interaction of Gprotein subunits with Ca channels using FRET imaging and other techniques.

Other projects in our laboratory are aim to understanding the molecular basis of neurodegenerative disease. We study Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), HIV-1 related dementia and other neuropathological conditions. In the case of HIV-1 infection, we have been examining the properties and functions of HIV-1 receptors on neurons. These receptors are known to be receptors for chemokines -small proteins that are known to direct the functions of the immune system. We have shown that neurons express many types of chemokine receptors and that activation of these receptors can produce both short and long term effects on neurons. Activation of chemokine receptors expressed by sensory neurons produces neuronal excitation and pain. Activation of chemokine receptors on hippocampal neurons has a prosurvival effect, whereas binding of HIV-1 to these receptors induces apoptosis. We are studying the molecular mechanisms that produce this diverse effects with a view to understanding the molecular basis for HIV-1 related dementias.

For lab information and more, see Dr. Miller’s faculty profile.

See Dr. Miller’s blog “The Keys to all Mythologies: Science, Medicine and Magic” to read articles concerning scientific topics of current interest as well as historical accounts of scientific issues.

Publications

See Dr. Miller's publications on PubMed.

Contact

Contact Dr. Miller at 312-503-3211.

Lab Staff

Research Faculty

Abdelhak Belmadani

Postdoctoral Fellow

Dongjun Ren

Graduate Students

Brittany Hopkins, Andrew Shum

Temporary Employees

Craig Rathwell, Laetitia Stumpf

 Loukia Parisiadou Lab

Investigating the cellular and molecular pathways by which mutations in genes linked to Parkinson’s Disease contribute to disease pathogenesis

Research Description

Parkinson’s disease (PD) has been classically considered a sporadic disease, however, it is now recognized to have a substantial genetic component. Interestingly, the same genes involved in the autosomal-dominantly inherited forms of PD such as SNCA and LRRK2 can act as risk factors in idiopathic cases of PD, as well. Therefore, studying the pathophysiological functions of these PD-related genes could provide valuable insights into the process of understanding the underlying pathogenic mechanisms of PD.

A large part of Dr. Parisiadou’s scientific efforts was focused on functionally characterizing the LRRK2 protein, and a number of relevant studies provided insights on the undetermined role of LRRK2 protein, as well as revealed an important functional interplay between SNCA and LRRK2. Based on the previous knowledge, Loukia Parisiadou’s research program is focused on the delineation of the contribution of LRRK2 and SNCA mutations in PD. To achieve this, a variety of mouse genetic, neuronal culture, histology, cell biology, biochemistry, and behavioral approaches will be utilized. Given the relevance of LRRK2 and α-synuclein with the sporadic forms of PD, our long-term research goal by interrogating α-synuclein and mainly LRRK2-dependent alterations at the cellular, network and behavioral levels is to appreciate the pathophysiology of PD. While there is still a long way to go in understanding the etiology of PD, LRRK2, and SNCA mutations have provided important insights into this process, and it is expected to have a crucial role to this effort for the following years to come.

Recent Findings

  • LRRK2 directs neurite morphology by the regulation of cytoskeletal dynamics in neurons
  • A functional interplay between alpha-synuclein and LRRK2, two gene products linked to autosomal-dominantly inherited forms of PD.
  • An emerging function of LRRK2 at the synapse: LRRK2 directs synaptogenesis, and neurotransmission.

Current projects

  • LRRK2-mediated deregulation of PKA activity results in aberrant dopaminergic and corticostriatal signaling in the striatal projection neurons.
  • Looking for novel therapeutic approaches for LRRK2 besides kinase inhibition: the identification of novel LRRK2 modifiers in specific sub-neuronal populations.
  • Unraveling the mechanistic details of α-synculein clearance.

For lab information and more, see Dr. Parisiadou's faculty profile and lab website.

Publications

See Dr. Parisiadou's publications on PubMed.

Contact

Contact Dr. Parisiadou at 312-503-2652.

Lab Staff

Postdoctoral Fellows

Chuyu Chen, Bharanidharan Shanmugasundaram

Technical Staff

Clayton Pedigo, Kamila Wisniewska

 Murali Prakriya Lab

Investigating intracellular calcium signaling

Prakriya Lab

Research Description

Research in the laboratory of Murali Prakriya, PhD, is focused on the molecular and cellular mechanisms of intracellular calcium (Ca2+) signaling. Ca2+ is one of the most ubiquitous intracellular signaling messengers, mediating many essential functions including gene expression, chemotaxis and neurotransmitter release. Cellular Ca2+ signals generally arise from the opening of Ca2+ permeable ion channels, a diverse family of membrane proteins. We are studying Ca2+ signals arising from the opening of a Ca2+ channel sub-type known as the store-operated Ca2+ channel (SOC). SOCs are found in the plasma membranes of virtually all mammalian cells and are activated through a decrease in the calcium concentration ([Ca2+]) in the endoplasmic reticulum (ER), a vast membranous network within the cell that serves as a reservoir for stored calcium. SOC activity is stimulated by a variety of signals such as hormones, neurotransmitters and growth factors whose binding to receptors generates IP3 to cause ER Ca2+ store depletion.

The best-studied SOC is a sub-type known as the Ca2+ release activated Ca2+ (CRAC) channel. CRAC channels are widely expressed in immune cells and generate Ca2+ signals important for gene expression, proliferation and the secretion of inflammatory mediators. Loss of CRAC channel function due to mutations in CRAC channel genes leads to a devastating immunodeficiency syndrome in humans. A major effort in our lab is to understand the molecular mechanisms of CRAC channel function.

Recent Findings

Despite the fact that SOCs are found in practically all cells, their properties and functions outside the immune system remain largely unexplored. In order to fill this gap, we have begun investigation of SOC properties and their functions in two major organ systems: in the brain and the lung.

  • Neural stem cells (NSCs) express SOCs; robust Ca2+ signals arise from their activation, indicating that SOCs are a major route of Ca2+ entry in NSCs
  • CRAC channels serve as a major route of Ca2+ entry in lung epithelial cells; CRAC channel activation leads to robust activation of NFAT and the production of proinflammatory cytokines

For lab information and more, see Dr. Prakriya’s faculty profile and lab website.

Publications

See Dr. Prakriya's publications on PubMed.

Contact

Contact Dr. Prakriya at 312-503-7030.

Lab Staff

Research Faculty

Megumi Yamashita

Postdoctoral Fellows

Kotaro Hori, Mehdi Maneshi, Nisha Shrestha 

Graduate Students

Michaela Novakovic, Andrew Shum, Ann Toth, Priscilla Yeung

Technical Staff

Natalie Bernstein, Chelsea Maguire

 Antonio Sanz-Clemente Lab

Investigating molecular mechanisms underlying glutamate receptors trafficking in normal and altered conditions

Research Description

Neurons communicate with each other at synapses, extremely specialized and plastic structures able to adjust both quantitatively and qualitatively to correctly respond to a changing environment. The majority of neuronal communication is mediated by the activation of glutamate receptors (GluRs), which triggers mechanisms able to induce changes at synaptic level that are thought to underlie higher cognitive functions. Accordingly, GluRs are extremely well regulated in a cell- and synapse-specific manner. Several mechanisms including the control of expression/degradation level, intracellular trafficking or channel properties work coordinately to regulate GluRs. Not surprisingly, an aberrant GluR trafficking and/or function is a shared hallmark for many neurological disorders, including Alzheimer’s disease, Huntington’s disease, schizophrenia and autism.

The Sanz-Clemente Lab is interested in the molecular mechanisms underlying GluR trafficking in normal and altered conditions. We use a multidisciplinary approach including biochemistry, cell and molecular biology, pharmacology as well as a variety of imaging techniques and the analysis of genetically-altered mouse lines for elucidating how GluRs are controlled during development, in response to experience or other stimuli and what is their impact on synaptic function. Similarly, we investigate how the dysregulation of these mechanisms lead to synaptic alterations and, eventually, to neurological disorders. Current research focuses on NMDA Receptor (NMDAR) regulation and its role in the pathogenesis of Alzheimer’s disease.

Recent Findings

The synaptic NMDAR subunit composition changes from predominantly GluN2B-containing to GluN2A-containing NMDARs during synaptic maturation and in response to activity and experience. This is an evolutionally conserved process that occurs in many brain areas and has important consequences in synaptic plasticity and intracellular signaling pathways.

  • We have identified the phosphorylation within the GluN2B PDZ ligand by casein kinase 2 as a critical determinant for the NMDAR subunit switch, by promoting GluN2B internalization and allowing GluN2A insertion into synaptic sites.
  • We have reported a novel structural role for CaMKII, acting as a scaffolding protein able to couple GluN2B and casein kinase 2 in response to activity, which controls NMDAR synaptic content.

Current Projects

  • Investigating the molecular mechanisms controlling the balance between synaptic and extrasynaptic NMDARs and its role in the pathogenesis of Alzheimer’s disease
  • Investigating the molecular mechanisms underlying synapse unsilencing during development
  • Studying the differential reorganization of synaptic protein content by typical and atypical antipsychotic drugs

For lab information and more, see Dr. Antonio Sanz-Clemente's faculty profile and lab website.

Publications

See Dr. Sanz-Clemente's publications on PubMed.

Contact

Contact Dr. Sanz-Clemente at 312-503-4896.

Lab Staff

Postdoctoral Fellow

JieJie Wang, Luca Zangrandi 

Graduate Student

Andrew Chiu

Technical Staff

Levi Barse

 Jeffrey Savas Lab

Research in the Savas lab is aimed at accelerating our understanding of the proteins and proteomes responsible for neurodevelopmental and neurodegenerative diseases.

Research Description

We use biochemistry with discovery-based mass spectrometry to identify the protein perturbations which drive synaptopathies and proteinopathies. Groups of perturbed proteins serve as pathway beacons which we subsequently characterizes in hopes of finding new pathogenic mechanisms and potential future therapeutic targets.

For more information view the faculty profile of Jeffrey Savas, PhD or the Savas Lab website.

Publications

Please see Dr. Savas' publications on PubMed.

Contact Information

Jeffrey N Savas, PhD
Assistant Professor in Neurology
312-503-3089

Lab Staff

Postdoctoral Fellows

Yi-Zhi Wang, PhD

Technical Staff

Laith Ali

Kira Alia Cozzolino

Sam Smukowski

Graduate Students

Undergraduate Students

Lap-Heng Keung

 Eugene Silinsky Lab

Studying neuromuscular transmission and its modulation by adenosine derivatives under normal conditions and in disease

Research Description

Dr. Silinsky, assisted by his collaborator and laboratory co-director Dr. Timothy Searl, Research Assistant Professor, studies neuromuscular transmission and its modulation at both voluntary (skeletal) and involuntary (autonomic) neuromuscular junctions.

Nerve endings communicate with their receiving cells by the secretion of primary neurotransmitter substances and also regulate their own activity by the co-release of neuromodulatory substances. Adenosine derivatives are such modulatory substances. Indeed, we now know that most synapses in the vertebrate nervous system are responsive to physiological levels of extracellular adenosine derivatives.

The Silinsky laboratory studies the effects of adenosine and adenosine triphosphate (ATP) on the functions of the peripheral nervous system. These molecules were originally implicated as important components of metabolic pathways and in the subtle control of the rate of chemical reactions. However, adenosine and ATP have been found by the Silinsky laboratory and other laboratories to be essential modulators of neuronal function and also to be neurotransmitters in disease states.

For example, we have found that adenosine, derived from the ATP released from nerve endings after repetitive activation, is an important mediator of the fatigue of our voluntary muscles. In addition, ATP may be the cause of overactive bladder, as ATP is released from overactive bladder and then acts on ATP-gated ion channels to cause the bladder muscle over-activity. These ATP-gated channels are absent from normal bladder muscles but their presence in disease states overwhelms the normal communication between nerve and bladder muscle and appears to be a major cause of the debilitating symptoms suffered by overactive bladder patients. We are also studying the effects of botulinum toxins, which are used to treat overactive bladder, as therapeutic tools and as tools to study modulation of neurotransmitter secretion at nerve endings.

Important Findings

  • The first discovery that ATP is released together from motor nerve endings with the neurotransmitter acetylcholine and in quantal units (citations 1 and 2 below). This work led to our finding of specific adenosine receptors on nerve endings (the first evidence for adenosine receptors on any neuron-citation 3) and the finding that ATP, and after hydrolysis to adenosine, acts on specific adenosine receptors to mediate neuromuscular depression (citation 4).
  • Evidence that botulinum toxins can either increase or obtund modulation of calcium currents in nerve endings. Citation 5 was a featured PNAS article (with the supplementary material providing a detailed description of the different botulinum toxin fractions at motor nerve endings to skeletal muscle). This article also describes differences in the effects of botulinum toxins between wild type and mutant mice.
  • Evidence that the traditional textbook assumption that neuromuscular depression during low frequency clinical assessment conditions is due to depletion of neurotransmitter is wrong-this depression is due to a decrease in nerve terminal calcium currents (Citation 6).
  • Evidence that adenosine receptors on nerve ending can be constitutively active in the absence of adenosine (Citation 7).
  • Evidence that the nerve endings innervating the mammalian bladder are primed in a manner similar to other synapses in the peripheral and central nervous systems (citation 8).

Citations to the Important Findings:

1.  Silinsky EM (1975) On the association between transmitter secretion and the release of adenine nucleotides from mammalian motor nerve terminals. J Physiol 247: 145 162.
2.  Silinsky EM & Redman RS (1996) Synchronous release of ATP and neurotransmitter within milliseconds of a motor nerve impulse in the frog. J Physiol 492.3: 815-822.
3.  Silinsky EM (1980) Evidence for specific adenosine receptors at cholinergic nerve endings. Brit J Pharmacol 71: 191-194,
4.  Redman RS & Silinsky EM (1994) ATP released together with acetylcholine as the mediator of neuromuscular depression at frog motor nerve endings. J Physiol 477.1:117-127.
5.  Silinsky EM (2008) Selective disruption of the mammalian secretory apparatus enhances or eliminates calcium current modulation in nerve endings. Proc Natl Acad Sci USA  105: 6427-32.
6.  Silinsky EM (2013) Low frequency neuromuscular depression is a consequence of a reduction in nerve terminal Ca2+ currents at mammalian motor nerve endings. Anesthesiology 119:326-334.
7.  Searl TJ & Silinsky EM (2012) Evidence for constitutively-active adenosine receptors at mammalian motor nerve endings. Eur J Pharmacol 685: 38-41.
8.  Searl TJ & Silinsky EM (2012) Modulation of purinergic neuromuscular transmission by phorbol dibutyrate is independent of protein kinase C in the murine urinary bladder. J Pharmacol Exp Ther 342:1-6.

Current and Planned Projects

  • Investigating the effects of adenosine antagonists as potential treatments for diseases associated with excessive neuromuscular fatigue (e.g. myasthenia gravis) and for botulinum toxin poisoning  
  • Investigating the effects of aging at the neuromuscular junction using animal models (in collaboration with Dr. Richard Lieber’s laboratory at Shirley Ryan AbilityLab)
  • Investigating the causes of overactive bladder in mouse models and in human biopsies (in collaboration with the Department of Urology at Northwestern University and Southern Illinois University) as well as the potential therapeutic advantages of different botulinum toxin serotypes in bladder disorders.

For lab information and more, see Dr. Silinsky's faculty profile.

Publications

See Dr. Silinsky's publications on PubMed.

Contact

Contact Dr. Silinsky at 312-503-8287.

Lab Staff

Research Faculty

Timothy Searl, PhD

 Geoffrey Swanson Lab

Studying glutamate receptors in the modulation of neurotransmission and induction of synaptic plasticity

Research Description

Geoffrey Swanson’s, PhD, laboratory studies the molecular and physiological properties of receptor proteins that underlie excitatory synaptic transmission in the mammalian brain. Current research focuses primarily on understanding the roles of kainate receptors, a family of glutamate receptors whose diverse physiological functions include modulation of neurotransmission and induction of synaptic plasticity. We are also interested in exploring how kainate receptors might contribute to pathological processes such as epilepsy and pain. The laboratory investigates kainate receptor function using a diverse group of techniques that include patch-clamp electrophysiology, selective pharmacological compounds, molecular and cellular techniques and gene-targeted mice.

Current Projects

  • Isolation and characterization of new marine-derived compounds that target glutamate receptors
  • Kainate receptors in hippocampal synaptic transmission
  • Mechanisms of kainate receptor assembly and trafficking

For lab information and more, see Dr. Swanson’s faculty profile and lab website.

Publications

See Dr. Swanson's publications on PubMed.

Contact

Contact Dr. Swanson at 312-503-1052.

Lab Staff

Neurology Fellow

William Nobis

Postdoctoral Fellows

Tristan Hedrick

Graduate Student

Erica Binelli

Technical Staff

Helene Lyons-Swanson, Jacob Stolz

Visiting Scholar

Toshiyuki Ishii

 Martin Watterson Lab

Focusing on the role of protein phosphorylation pathways in disease onset and progression and their potential as drug discovery targets

Research Description

Current Projects

The role of calmodulin (CaM) mediated signal transduction pathways in physiology and pathophysiology

  • Using of emerging technologies to understand how CaM and a CaM-regulated enzyme could be encoded, expressed, regulated and assembled into a calcium signal transduction complex
  • Using of integrative (in vivo) chemical biology and molecular genetics to gain insight into how landmark CaM-regulated protein kinases are involved in physiology and pathophysiology

Integrative chemical biology and development of novel therapeutics for attenuation of disease progression

  • Using the “smart chemistry” approach integrated with “smart biology” screens for rapid discovery of novel small molecules with potential use in targeting pathophysiology progression related to diseases ranging from neurological disorders, cancer, inflammatory conditions, cardiovascular and pulmonary disease
  • Discovering and developing novel small molecule compounds that selectively attenuate the increased production of proteins called proinflammatory cytokines, which can cause tissue injury and disease when produced in excess

We ultimately hope to find, by targeting pathophysiology mechanisms which contribute to disease progression, a series of novel small molecules with potential to be effective against a variety of disorders.

For lab information and more, see Dr. Watterson’s faculty profile.

Contact

Contact Dr. Watterson at 312-503-0657.

Lab Staff

Adjunct Professor

Jeff Pelletier

Senior Research Associate

Saktimayee Roy

Research Lab Manager

James Schavocky

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