Northwestern University Feinberg School of Medicine
Center for Autism and Neurodevelopment
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Mouse and Human Neuronal Models

The recently-uncovered genetic causes of autism and related disorders can provide insight into their neurobiological bases. Mouse models or human neurons generated from patient-derived induced pluripotent stem cells (iPSC) are being used by Center for Autism and Neurodevelopment faculty to understand the function of these genes in shaping the development of brain circuits and how their improper function may derail neurodevelopment. Genetic causes investigated include the 16p11.2 copy number variation in autism and schizophrenia, FMRP1 in fragile-X syndrome, MECP2 in Rett and Asperger syndromes and CNTNAP2, GRIN2B, SCN2A and ANK2 in autism.

 Anis Contractor Lab

Seeking to understand the link between synaptic dysfunction and neuropsychiatric disorders and neurodevelopmental disorders

Research Description

Research in our laboratory is directed at understanding the mechanisms of synaptic transmission and plasticity and the role that glutamate receptors have in brain function and pathology. We use a multidisciplinary approach including in vitro electrophysiological recording, optogenetics, cellular imaging, mouse behavior and biochemical techniques. We ultimately seek to understand the link between synaptic dysfunction and neuropsychiatric disorders and neurodevelopmental disorders. Current projects are investigating altered synaptic signaling in mouse models of obsessive compulsive disorder, schizophrenia and fragile X syndrome.

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

Publications

See Dr. Contractor's publications on PubMed.

Contact

Contact Dr. Contractor 312-503-1843 or the lab at 312-503-0276.

Lab Staff

Research Faculty

Jian Xu

Postdoctoral Fellows

Charlotte Castillon, Qionger He, John Marshall, Toshihiro Nomura, Shintaro Otsuka, Christine Remmers

Graduate Students

Olga Melendez-Fernandez, Chad Morton, Yiwen Zhu

Technical Staff

Damonick Baxter, Stephen Kraniotis 

 Alicia Guemez-Gamboa Lab

Identifying and investigating novel molecular bases of cellular recognition that govern neuronal circuit assembly during human development and disease.

Research Description

Developing neurons integrate into functional circuits through a series of cell recognition events, which include neuronal sorting, axon and dendrite patterning, synaptic selection, among others. Our research focuses on cell-surface recognition molecules that mediate interactions between neurons to discriminate and select appropriate targets in the developing brain. Additionally, we seek to uncover novel mechanisms of neural recognition that lead to brain connectivity defects in humans. To explore the broader roles for cell recognition molecules and their pivotal function in neural circuit development, our lab takes advantage of a battery of modern laboratory techniques. These approaches include animal and stem cell disease modeling, as well as next-generation sequencing and CRISPR/Cas9 gene editing. Identifying fundamental principles of cellular recognition in wiring circuits contributes to our understanding of neurological disorders and how neuronal dysfunction arises from aberrations during development of the human brain.

For lab information and more, see Dr. Guemez-Gamboa's faculty profile and lab website.

Publications

See Dr. Guemez-Gamboa's publications on PubMed.

Contact

Contact Dr. Guemez-Gamboa at 312-503-0752.

Lab Staff

Postdoctoral Fellows

Nadya Gabriela Languren, Jennifer Rakotomamonjy

Technical Staff

Sean McDermott, Niki Sabetfakhri, Davis Thomas

 Evangelos Kiskinis Lab

Our laboratory investigates the molecular mechanisms that give rise to neurological diseases using human stem cell-derived neuronal subtypes.

Research Description

The broad objective of our laboratory is to understand the nature of the degenerative processes that drive neurological disease in human patients. We are primarily interested in Amyotrophic Lateral Sclerosis (ALS), Epileptic Syndromes as well as the age-associated changes that take place in the Central Nervous System (CNS). We pursue this objective by creating in vitro models of disease. We utilize patient-specific induced pluripotent stem cells and direct reprogramming methods to generate different neuronal subtypes of the human CNS. We then study these cells by a combination of genomic approaches and functional physiological assays. Our hope is that these disease model systems will help us identify points of effective and targeted therapeutic intervention.

Publications

View Dr. Kiskinis' publications at PubMed

For more information view the faculty profile of Evangelos Kiskinis, PhD, or the Evangelos Kiskinis Lab site.

Contact Information

Evangelos Kiskinis, PhD
Assistant Professor of Neurology

 Peter Penzes Lab

Studying the molecular and cellular mechanisms that control the formation and modification of dendritic spines in the mammalian brain

Research Description

Research in my laboratory centers on the molecular and cellular mechanisms that control the formation and modification of dendritic spines in the mammalian brain. These mechanisms underlie the normal development and plasticity of the brain, and contribute to higher brain functions, including cognitive, social, and communication behavior. However, when these mechanisms go awry, they lead to mental and neurological disorders. Our analysis integrates multiple organizational levels, from molecular, cellular, circuit, and rodent models, to human subjects. We employ both a “translational” strategy, utilizing basic mechanistic data we generate to understand disease pathogenesis, and a “reverse-translational” strategy, in which genetic, neuropathological, and imaging studies in human subjects help guide the discovery of novel mechanistic insight. The ultimate goal of these studies is to develop therapeutic approaches to prevent or reverse neuropsychiatric disorders, by targeting mechanisms that control dendritic spines and synapses.

Projects within Our Lab

1. Mechanistic studies on the molecular mechanisms of dendritic spine plasticity. This line of research aims to identify and elucidate functions of novel molecular regulators of synaptic circuit modification during the lifespan. We investigate the formation, remodeling, and elimination of spiny synapses in neurons using both in vitro and in vivo models. We are particularly interested in signaling, adhesion, and scaffolding molecules that control cell-to-cell communication and mediate intracellular signaling by neurotransmitter receptors. My laboratory continues to investigate small GTPase pathways and the roles of guanine-nucleotide exchange factors, such as kalirin and Epac2, and their downstream targets Rac, PAK, Rap and Ras. In addition, we have made important contributions to understanding how synaptic activity controls synapse size and strength through a pathway involving NMDA receptors, CaMKII, kalirin, Rac1 and actin, how rapid synaptic plasticity in the brain is regulated by locally synthesized estrogen, how adhesion molecules including N-cadherin control synapse size and strength, and how dopamine and neuroligin control synapse stability though Epac2 and Rap1.

2. Translational and reverse-translational studies on the molecular substrates of dendritic spine pathology. Investigations of genetic, neuropathological, and neuromorphological alterations in human subjects with psychiatric disorders have started to reveal the pathogenic mechanisms behind these illnesses, and are also guiding the discovery of unexpected basic mechanisms of brain development and function. Through studies performed in the lab and through collaborations, we investigate molecular and cellular alterations occurring in patients with schizophrenia, bipolar disorder, autism, and Alzheimer’s disease. We then use model systems, such as neuronal cultures or mice, to elucidate the functions and pathogenic mechanisms of key molecules. We are currently investigating the basic synaptic functions of several leading mental disorder risk genes, to understand how they contribute to normal brain function and to synapse pathology. Conversely, many molecules we have been studying in the lab have more recently been implicated in the pathogenesis of mental disorders through independent neuropathological or genetic studies. We have shown that molecules that control basic synapse structural plasticity, such as kalirin and Epac2, functionally interact with leading mental disorder risk molecules, such as neuregulin1, ErbB4, DISC1, 5HT2A receptors, dopamine receptors, neuroligin, and Shank3. We have generated mutant mice in which kalirin or Epac2 are ablated, and have shown that these molecules control behaviors relevant for mental disorders, such as sociability, working memory, sensory motor gating, and vocalizations. These animal models can thus help to understand the synaptic substrates of specific aspects of mental disorders. To investigate the abnormal regulation of these molecular pathways in schizophrenia, autism, Alzheimer’s disease, and the impact of these molecular abnormalities on disease phenotypes in human subjects, we are collaborating with neuropathologists, brain imaging experts, and geneticists who investigate human subjects.

Potential Clinical Implications of Our Work

Therapeutic reversal of neuropsychiatric disease by targeting synaptic connectivity. By harnessing the knowledge from our basic and reverse-translational studies, my goal is to develop novel therapeutic approaches to prevent, delay, or reverse the course of mental and neurodegenerative disorders. Because abnormal synaptic connections play central roles in the pathogenesis of schizophrenia, autism, and Alzheimer’s disease, pharmacological targeting of key molecules implicated in synaptic plasticity and pathology can rescue disease associated abnormalities, and thereby influence the outcome of the disease. We are currently developing transgenic animal models to validate synaptic signaling molecules as therapeutic targets in mental disorders. We are also developing cellular assays which we will use in high-throughput screens for small-molecule regulators of synapse remodeling. Our goal is to identify small-molecule regulators of synapse remodeling which can be taken into clinical trials as therapeutics aimed at reversing synaptic deficits, and thus cognitive dysfunction, in mental disorders.

Our Facilities

In our studies, we employ a multidisciplinary approach, using an array of methods that include advanced cellular and in vivo microscopy, biochemistry, electrophysiology, manipulations of gene expression in vivo, mouse behavioral analysis, circuit mapping, and human genetics and neuropathology.

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

Publications

See Dr. Penzes' publications on PubMed.

Contact

Contact Dr. Penzes at 312-503-5379.

Lab Staff

Postdoctoral Fellows

Daniel Bermingham, Lorenza Culotta, Marc Forrest, Maria Dolores Martin de SaavedraKristoffer MyczekEuan ParnellNicolas Piguel, Christopher Pratt, Marc Dos Santos, Lauren Shapiro, Sehyoun Yoon, Colleen Zaccard 

Graduate Students

Ruoqi Gao, Theron Russell

Technical Staff

Leonardo Dionisio, Katherine Horan, Hiba Jalloul, Daniel Loizzo, Emmarose McCoig

Visiting Scholar

Roos Voorn

Temporary Staff

Vikram Bagchi, Amy Song

 Jelena Radulovic Lab

Principal Investigator: Jelena Radulovic, MD, PhD

 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

 

 Gordon MG Shepherd Lab

Applying multiple tools of quantitative synaptic circuit analysis to elucidate the functional ‘wiring diagrams’ of neocortical neurons in the mouse motor cortex

Research Description 

Synaptic circuits in motor areas of neocortex engage in neural operations underlying many aspects of cognition and behavior – motor control, executive functions, working memory, and more – yet circuit organization at the synaptic, cellular, and molecular levels remains poorly understood in agranular cortex. What is the functional organization of these synaptic pathways? What cellular and circuit-level operations do neurons in these perform? How do these local circuits communicate with each other and how do they interact with subcortical systems in the basal ganglia and thalamus? The focus of our laboratory is to apply multiple tools of quantitative synaptic circuit analysis to elucidate the functional ‘wiring diagrams’ of neocortical neurons in motor cortex. We use laser scanning photostimulation (LSPS) microscopy, based on glutamate uncaging and channelrhodopsin-2 excitation, for rapid functional mapping of synaptic pathways onto single neurons in brain slices of motor cortex. We are also applying a variety of circuit analysis tools in efforts to identify circuit-level mechanisms in mouse models of disease, including autism, Rett syndrome, epilepsy, and motor neuron diseases.

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

Publications

See Dr. Shepherd's publications on PubMed.

Contact

Contact Dr. Shepherd at 312-503-1342 or the lab at 312-503-0753.

Lab Staff

Postdoctoral fellows

John Barrett, Xiaojian LiNaoki Yamawaki

Graduate student

KuangHua Guo

Visiting Scholar

Laurie Lambot

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