Basic Biology

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.

Research Faculty: John Armstrong, John Marshall, Jian Xu

Postdoctoral Fellows: Charlotte Castillon, Morgane Chiesa, Toshihiro Nomura, Shintaro Otsuka, Yiwen Zhu

Graduate Students: Matt Barraza, Nai-Hsing Yeh

Research Description

Early studies into the neuromodulatory information encoded by midbrain dopamine neurons suggested that a key function of dopamine is to transmit reward prediction error signals - a measure of whether events were better or worse than expected based on previous experience. However, not all midbrain dopamine neurons appear to encode similar information in their activity patterns. For example, our research has shown that substantia nigra dopamine neurons differ in their responses to aversive stimuli depending on their projection target, a finding that comports with previous literature on heterogeneous dopamine firing patterns and further suggests that diversity in the dopamine system can be best understood in the context of specific circuits and behaviors. Building on this investigative framework, we are now working to correlate individual variability in dopamine-related behaviors with detailed structural and functional connectivity observations within the midbrain dopamine system. By using natural sources of variability in mouse behavior, we gain access to study the potentially large yet unexplored natural range of individual variation in the circuit organization of the midbrain dopamine system. By simultaneously obtaining whole-brain anatomical and functional neural circuitry datasets, we hope to build a comprehensive theory of how specific individual differences in the circuitry of the heterogeneous midbrain dopamine system support a diverse set of behaviors, including reinforcement learning, motivation, risk preference and addiction.

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

Publications

See Dr. Lerner's publications on PubMed.

Contact

Contact Dr. Lerner.

Lab Manager: Louis Van Camp

Postdoctoral Fellows: Ryan Kovaleski, Michael Schaid, Jillian Seiler, ManHua Zhu

Graduate Students: Gabriela Lopez, Nkatha Mwenda, Jacob Nadel

Post-Baccalaureate Research Fellow: Naeliz Lopez

Undergraduate Students: Baran Demir, Irene Son, Andrew Hou

Technical Staff: Venus Sherathiya

Research Description

Our laboratory investigates the neuronal circuits that underlie the functions of the hippocampus, which is a region of the brain involved in learning and memory.

In particular, we are interested in the roles played by specific cell types such as GABAergic interneurons and Cajal-Retzius cells in regulating network synchronization, synaptic plasticity, and in guiding the correct development of the hippocampal structural and functional architecture.

Our goal is to discover novel synaptic mechanisms that are of physiological relevance, but may also provide original insights for the pathogenesis of neurological diseases such as epilepsy and neurodevelopmental disorders, which often target the hippocampus.

We take advantage of an integrated approach combining several techniques such as paired recordings from anatomically identified neurons, optogenetic, immunohistochemistry, light and electron microscopy applied to wild-type and transgenic animals.

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

Publications

See Dr. Maccaferri's publications on PubMed.

Contact

Contact Dr. Maccaferri at 312-503-4358.

Research Faculty: Max Anstotz

Technical Staff: Jessica Sciaky

Research Description

The lab has two main research lines: mechanisms of neuronal excitability and organization of brain microcircuits.

We pursue these two wide basic science interests by investigating scientific questions with immediate potential for bench to bed translation. In particular, altered neuronal excitability is involved in important pathologies such as epilepsy, neurodegenerative diseases and neuropathic pain. Similarly, understanding the local brainstem networks that underlie the generation and regulation of breathing is a necessary step to understanding the mechanisms of SIDS (Sudden Infant Death Syndrome). Finally, we are interested in the identification of the role of unipolar brush cells, a recently discovered cell type of the cerebellar cortex, in cerebellar microcircuits.

To investigate these questions we use multiple techniques such as electrophysiological recordings from neurons and dendrites in brain slices and cultures, PCR analysis of gene expression, histochemical analysis of protein expression and optogenetic manipulations.

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

Publications

See Dr. Martina's publications on PubMed.

Contact

Contact Dr. Martina at 312-503-4654.

Research Faculty: Gabriella Sekerkova 

Postdoctoral Fellows: Soumil Dey, Jeehaeh Do, Rafiq Huda, Haram Kim

Graduate Students: Crystle Ashford, Taylor Jefferson

Technical Staff: Yen-Hsin Cheng

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.

• 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.
• 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.

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.

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.

Publications

See Dr. Penzes' publications on PubMed.

Contact

Contact Dr. Penzes at 312-503-5379.

Research Faculty: Marc Forrest, Euan Parnell, Sehyoun Yoon, Colleen Zaccard

Postdoctoral Fellows: Nicolas Piguel, Marc Dos Santos

Technical Staff: Jessica Christiansen Blair Eckman

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 store-operated Ca²⁺  channels (SOCs). 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 encoded by the Orai1 protein. 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. Our goals are to understand the molecular mechanisms of CRAC channel activation, and their physiological roles especially in the microglia and astrocytes of the brain, and in the airway epithelial cells of the lung.

Recent Findings

Despite the fact that CRAC channels 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 CRAC channel properties and their functions in two major organ systems: in the brain and the lung.

• In the brain, we are studying the role of CRAC channels for dendritic Ca²⁺ signaling in excitatory neurons of the hippocampus, and their role in synaptic plasticity and cognitive functions. We have found that CRAC channels formed by Orai1 are critical for amplifying glutamate receptor evoked calcium signals in dendritic spines of hippocampal neurons, and this step is essential for driving structural and functional measures of synaptic plasticity and cognitive processes involving learning and memory.
• In a second project, we are studying the role of CRAC channels in driving neuroinflammation. We have found that CRAC channels formed by Orai1 are essential for the production and release of proinflammatory cytokines and chemokines in microglia and astrocytes.  We are examining the relevance of this pathway for mediating inflammatory and neuropathic pain.
• A third project is examining the role of CRAC channels for mediating pro- and anti-inflammatory processes in the lung. We have found that CRAC channels are a major mechanism for mobilizing Ca²⁺ signals in lung epithelial cells, and the downstream production of both pro- and anti-inflammatory mediators. We are examining the relevance of this signaling for lung inflammation in the context of asthma.

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.

Research Faculty: Megumi Yamashita

Postdoctoral Fellows: Kirill Korshunov, Aashutosh Shetti

Graduate Students: Kaitlyn DeMeulenaere, Se’ Ferrell, Michaela Novakovic

Technical Staff: Megan Martin

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.

Graduate Student: Brynna Webb

Technical Staff: Helene Lyons-Swanson

Research Description

RNA Processing and Neurodegeneration: Accumulating evidence supports that aberrant RNA processing represents a general pathogenic mechanism for neurodegeneration, including dementia and amyotrophic lateral sclerosis (ALS). A number of RNA binding proteins (RBPs) have been associated with neurodegenerative diseases, especially various proteinopathies. Recent studies have defined TDP-43 and FUS proteinopathies, a group of heterogeneous neurodegenerative disorders overlapping with dementia, including frontotemporal lobar degeneration (FTLD) and ALS. Several important questions drive our research: what is physiological function of these RBPs? What are the fundamental mechanisms by which genetic mutations in or aberrant regulation of these RBPs cause neural damage? What are the earliest detectable molecular and cellular events that reflect the neural damage in these devastating neurological diseases? How to reverse/repair the neural damage and slow down the progression of these devastating diseases.

To address these questions, we have established cellular and animal models for both TDP-43 and FUS proteinopathies (Li et al, 2010;Barmada et al, 2010; Chen et al, 2011; Fushimi et al, 2011). Using combined biochemical, biophysical, molecular biology and cell biology approaches, we have begun to examine the molecular pathogenic mechanisms underlying neurotoxicity induced by TDP-43 and FUS. Our recent work using atomic force microscopy (AFM), electron microscopy (EM) and (NMR) approaches has shown the biochemical, biophysical and structural similarities between TDP-43 and classical amyloid proteins (Guo et al, 2011; Xu et al, 2013; Bigio et al, 2013). Our study has defined a minimal amyloidogenic region at the carboxyl terminal domain of TDP-43 that is sufficient for amyloid fibril formation and neurotoxicity (Guo et al, 2011; Zhu et al, unpublished). Using cellular and animal models for FUS proteinopathy, we have begun to identify the earliest detectable cellular damage caused by mutations in and overexpression of the human FUS gene. Our data have provided new insights into pathogenic mechanisms underlying these proteinopathies and suggested candidate targets for developing therapeutic approaches.

A critical step in mammalian gene expression is the removal of introns by the process of pre-mRNA splicing. Alternative pre-mRNA splicing, the process of generating multiple mRNA transcripts from a single genetic locus by alternative selection of distinct splice sites, is one of most powerful mechanisms for genetic diversity and an excellent means for fine-tuning gene activity. Many genes critical for neuronal survival and function undergo extensive alternative splicing. Splicing defects play important roles in neurodegenerative disorders such as dementia and motor neuron diseases. For example, splicing mutations in the human tau gene and imbalance of tau splicing isoforms lead to frontotemporal lobar degeneration with tau-positive pathology (FTLD-tau). To understand mechanisms underlying FTLD-tau, we have set up a model system and developed a number of biochemical, molecular and cell biological assays to study alternative splicing of the human tau gene. Our work has led to the identification of a number of cis-elements and trans-acting RBPs controlling tau alternative splicing (Kar et al, 2006; Wu et al, 2006; Kar et al, 2011; Ray et al, 2011). Our experiments have begun to reveal previously unknown players in FTLD-tau and provided new candidate target genes for developing therapeutic strategy (Donahue et al, 2006; unpublished).

Molecular Mechanisms Regulating Axon Guidance, Cell Migration & Tumor Metastasis: Another line of our research focuses on the cellular and molecular mechanisms regulating cell migration and cancer metastasis. Previous studies from our group and others led to the discovery of Slit as a prototype of neuronal guidance cue. Our studies have shown that Slit interacts with Roundabout (Robo) and acts as a chemorepellent for axons and migrating neurons (Wu et al, 1999; Li et al, 1999;Yuasa-Kawada et al, 2009). Our work has demonstrated that Slit-Robo signaling modulates chemokines and inhibits migration of different types of cells, including cancer cells. The observation that Slit is frequently inactivated in a range of tumors suggests an important role of Slit in tumor suppression. We have established several assays and shown that Slit inhibits invasion and migration of cancer cells, including breast cancer, glioma and prostate cancer. We are using combined molecular and cell biology approaches to dissecting Slit-Robo signaling in neuronal guidance and tumor suppression. Our research has provided new insights into signal transduction pathways mediating Slit function. Enhancing or activating the endogenous mechanisms that restrict or suppress cancer invasion/metastasis will likely provide novel approaches to cancer metastasis. 

For more information please view the faculty profile of Jane Wu, MD, PhD or visit the Wu Lab website.

Publications

View a full list of publications by Jane Wu at PubMed.

Contact

Email Jane Wu, MD, PhD 

Phone: 312-503-0684