Neurosciences Commons^™

Nanoscale Rules Governing The Organization Of Glutamate Receptors In Spine Synapses Are Subunit Specific, Martin Hruska, Rachel E Cain, Matthew B Dalva

Department of Neuroscience Faculty Papers

Heterotetrameric glutamate receptors are essential for the development, function, and plasticity of spine synapses but how they are organized to achieve this is not known. Here we show that the nanoscale organization of glutamate receptors containing specific subunits define distinct subsynaptic features. Glutamate receptors containing GluA2 or GluN1 subunits establish nanomodular elements precisely positioned relative to Synaptotagmin-1 positive presynaptic release sites that scale with spine size. Glutamate receptors containing GluA1 or GluN2B specify features that exhibit flexibility: GluA1-subunit containing AMPARs are found in larger spines, while GluN2B-subunit containing NMDARs are enriched in the smallest spines with neither following a strict …

Treatment-Specific Hippocampal Subfield Volume Changes With Antidepressant Medication Or Cognitive-Behavior Therapy In Treatment-Naive Depression., Hua-Hsin Tai, Jungho Cha, Faezeh Vedaei, Boadie W Dunlop, W Edward Craighead, Helen S Mayberg, Ki Sueng Choi

Department of Neuroscience Faculty Papers

Background: Hippocampal atrophy has been consistently reported in major depressive disorder with more recent focus on subfields. However, literature on hippocampal volume changes after antidepressant treatment has been limited. The first-line treatments for depression include antidepressant medication (ADM) or cognitive-behavior therapy (CBT). To understand the differential effects of CBT and ADM on the hippocampus, we investigated the volume alterations of hippocampal subfields with treatment, outcome, and chronicity in treatment-naïve depression patients. Methods: Treatment-naïve depressed patients from the PReDICT study were included in this analysis. A total of 172 patients who completed 12 weeks of randomized treatment with CBT (n …

The Ephb2 Receptor Uses Homotypic, Head-To-Tail Interactions Within Its Ectodomain As An Autoinhibitory Control Mechanism, Yan Xu, Dorothea Robev, Nayanendu Saha, Bingcheng Wang, Matthew B. Dalva, Kai Xu, Juha P. Himanen, Dimitar B. Nikolov

Department of Neuroscience Faculty Papers

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell–cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell–cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph–ephrin recognition have been previously revealed and it has been documented that ephrin binding …

Neuronal Nsun2 Deficiency Produces Trna Epitranscriptomic Alterations And Proteomic Shifts Impacting Synaptic Signaling And Behavior., J Blaze, A Navickas, H L Phillips, S Heissel, A Plaza-Jennings, S Miglani, H Asgharian, M Foo, C D Katanski, C P Watkins, Z T Pennington, B Javidfar, S Espeso-Gil, B Rostandy, H Alwaseem, C G Hahn, H Molina, D J Cai, T Pan, W D Yao, H Goodarzi, F Haghighi, S Akbarian

Department of Neuroscience Faculty Papers

Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m⁵C levels, resulting in deficits in expression of 70% of tRNA^Gly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired …

Caldag-Gefi Mediates Striatal Cholinergic Modulation Of Dendritic Excitability, Synaptic Plasticity And Psychomotor Behaviors., Jill R. Crittenden, Shenyu Zhai, Magdalena Sauvage, Takashi Kitsukawa, Eric Burguière, Morgane Thomsen, Hui Zhang, Cinzia Costa, Giuseppina Martella, Veronica Ghiglieri, Barbara Picconi, Karen A. Pescatore, Ellen M. Unterwald, Walker S. Jackson, David E. Housman, S. Barak Caine, David Sulzer, Paolo Calabresi, Anne C. Smith, D. James Surmeier, Ann M. Graybiel

Department of Neuroscience Faculty Papers

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. …

Conservation And Innovation: Versatile Roles For Lrp4 In Nervous System Development., Alison T. Depew, Timothy J. Mosca

Department of Neuroscience Faculty Papers

As the nervous system develops, connections between neurons must form to enable efficient communication. This complex process of synaptic development requires the coordination of a series of intricate mechanisms between partner neurons to ensure pre- and postsynaptic differentiation. Many of these mechanisms employ transsynaptic signaling via essential secreted factors and cell surface receptors to promote each step of synaptic development. One such cell surface receptor, LRP4, has emerged as a synaptic organizer, playing a critical role in conveying extracellular signals to initiate diverse intracellular events during development. To date, LRP4 is largely known for its role in development of the …

Infection And Risk Of Parkinson's Disease, Richard Jay Smeyne, Alastair J Noyce, Matthew D. Byrne, Rodolfo Savica, Connie Marras

Department of Neuroscience Faculty Papers

Parkinson's disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential risk factor, and there is supporting although not entirely consistent epidemiologic and basic science evidence to support its role. Encephalitis caused by influenza has included parkinsonian features. Epidemiological evidence is most compelling for an association between PD and hepatitis C virus. Infection with Helicobacter pylori may be associated not only with PD risk but also response to levodopa. Rapidly evolving knowledge regarding the role of the microbiome also suggests a role of resident bacteria …

A High Affinity, Partial Antagonist Effect Of 3,4-Diaminopyridine Mediates Action Potential Broadening And Enhancement Of Transmitter Release At Nmjs, Kristine S Ojala, Scott P Ginebaugh, Man Wu, Evan W Miller, Gloria Ortiz, Manuel Covarrubias, Stephen D Meriney

Department of Neuroscience Faculty Papers

3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-Approved treatment for neuro muscular weakness caused by Lambert-Eaton myasthenic syn drome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the pre synaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-Target agonist effect on the Cav1 subtype ("L-Type") of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release …

Sleep Induction By Mechanosensory Stimulation In Drosophila., Arzu Öztürk-Çolak, Sho Inami, Joseph R. Buchler, Patrick D. Mcclanahan, Andri Cruz, Christopher Fang-Yen, Kyunghee Koh

Department of Neuroscience Faculty Papers

People tend to fall asleep when gently rocked or vibrated. Experimental studies have shown that rocking promotes sleep in humans and mice. However, the mechanisms underlying the phenomenon are not well understood. A habituation model proposes that habituation, a form of non-associative learning, mediates sleep induction by monotonous stimulation. Here, we show that gentle vibration promotes sleep in Drosophila in part through habituation. Vibration-induced sleep (VIS) leads to increased homeostatic sleep credit and reduced arousability, and can be suppressed by heightened arousal or reduced GABA signaling. Multiple mechanosensory organs mediate VIS, and the magnitude of VIS depends on vibration frequency …

Facial Grimace Testing As An Assay Of Neuropathic Pain-Related Behavior In A Mouse Model Of Cervical Spinal Cord Injury., Nicolette M Heinsinger, Gabrielle Spagnuolo, R Vivian Allahyari, Simon Galer, Tyler Fox, David A Jaffe, Samantha J Thomas, Lorraine Iacovitti, Angelo C Lepore

Department of Neuroscience Faculty Papers

A major portion of individuals affected by traumatic spinal cord injury (SCI) experience one or more types of chronic neuropathic pain (NP), which is often intractable to currently available treatments. The availability of reliable behavioral assays in pre-clinical models of SCI-induced NP is therefore critical to assess the efficacy of new potential therapies. Commonly used assays to evaluate NP-related behavior in rodents, such as Hargreaves thermal and von Frey mechanical testing, rely on the withdrawal response to an evoked stimulus. However, other assays that test spontaneous/non-evoked NP-related behavior or supraspinal aspects of NP would be highly useful for a more …

Covid-19-Associated Cns Demyelinating Diseases, Dhanashri Miskin, Md

Department of Neuroscience Faculty Papers

Neurological manifestations of SARS-CoV-2 infection are increasingly being recognized. The most common neurologic symptoms include headache, anosmia, and dysgeusia, but patients may also develop other central nervous system (CNS) diseases.

Combination Of A Gellan Gum-Based Hydrogel With Cell Therapy For The Treatment Of Cervical Spinal Cord Injury, Eduardo D Gomes, Biswarup Ghosh, Rui Lima, Miguel Goulão, Tiago Moreira-Gomes, Joana Martins-Macedo, Mark W Urban, Megan C Wright, Jeffrey M Gimble, Nuno Sousa, Nuno A Silva, Angelo C Lepore, António J Salgado

Department of Neuroscience Faculty Papers

Cervical spinal cord trauma represents more than half of the spinal cord injury (SCI) cases worldwide. Respiratory compromise, as well as severe limb motor deficits, are among the main consequences of cervical lesions. In the present work, a Gellan Gum (GG)-based hydrogel modified with GRGDS peptide, together with adipose tissue-derived stem/stromal cells (ASCs) and olfactory ensheathing cells (OECs), was used as a therapeutic strategy after a C2 hemisection SCI in rats. Hydrogel or cells alone, and a group without treatment, were also tested. Four weeks after injury, compound muscle action potentials (CMAPs) were performed to assess functional phrenic motor neuron …

Covid-19 And Possible Links With Parkinson's Disease And Parkinsonism: From Bench To Bedside, David Sulzer, Angelo Antonini, Valentina Leta, Anna Nordvig, Richard Jay Smeyne, James E Goldman, Osama Al-Dalahmah, Luigi Zecca, Alessandro Sette, Luigi Bubacco, Olimpia Meucci, Elena Moro, Ashley S Harms, Yaqian Xu, Stanley Fahn, K Ray Chaudhuri

Department of Neuroscience Faculty Papers

This Viewpoint discusses insights from basic science and clinical perspectives on coronavirus disease 2019 (COVID-19)/severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the brain, with a particular focus on Parkinson's disease. Major points include that neuropathology studies have not answered the central issue of whether the virus enters central nervous system neurons, astrocytes or microglia, and the brain vascular cell types that express virus have not yet been identified. Currently, there is no clear evidence for human neuronal or astrocyte expression of angiotensin-converting enzyme 2 (ACE2), the major receptor for viral entry, but ACE2 expression may be activated by inflammation, and …

Synaptic Dysfunction Induced By Glycine-Alanine Dipeptides In C9orf72-Als/Ftd Is Rescued By Sv2 Replenishment., Brigid K Jensen, Martin H Schuldi, Kevin Mcavoy, Katelyn A Russell, Ashley Boehringer, Bridget M Curran, Karthik Krishnamurthy, Xinmei Wen, Thomas Westergard, Le Ma, Aaron R. Haeusler, Dieter Edbauer, Piera Pasinelli, Davide Trotti

Department of Neuroscience Faculty Papers

The most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic hexanucleotide repeat expansion in the C9orf72 gene. In disease, RNA transcripts containing this expanded region undergo repeat-associated non-AUG translation to produce dipeptide repeat proteins (DPRs), which are detected in brain and spinal cord of patients and are neurotoxic both in vitro and in vivo paradigms. We reveal here a novel pathogenic mechanism for the most abundantly detected DPR in ALS/FTD autopsy tissues, poly-glycine-alanine (GA). Previously, we showed motor dysfunction in a GA mouse model without loss of motor neurons. Here, we demonstrate that mobile …

Antagonistic Regulation Of Circadian Output And Synaptic Development By Jetlag And The Dyschronic-Slowpoke Complex, Angelique Lamaze, James E.C. Jepson, Oghenerukevwe Akpoghiran, Kyunghee Koh

Department of Neuroscience Faculty Papers

Circadian output genes act downstream of the clock to promote rhythmic changes in behavior and physiology, yet their molecular and cellular functions are not well understood. Here we characterize an interaction between regulators of circadian entrainment, output, and synaptic development in Drosophila that influences clock-driven anticipatory increases in morning and evening activity. We previously showed the JETLAG (JET) E3 ubiquitin ligase resets the clock upon light exposure, whereas the PDZ protein DYSCHRONIC (DYSC) regulates circadian locomotor output and synaptic development. Surprisingly, we find that JET and DYSC antagonistically regulate synaptic development at the larval neuromuscular junction, and reduced JET activity …

Positive Surface Charge Of Glun1 N-Terminus Mediates The Direct Interaction With Ephb2 And Nmdar Mobility., Halley R. Washburn, Nan L. Xia, Wei Zhou, Yu-Ting Mao, Matthew B. Dalva

Department of Neuroscience Faculty Papers

Localization of the N-methyl-D-aspartate type glutamate receptor (NMDAR) to dendritic spines is essential for excitatory synaptic transmission and plasticity. Rather than remaining trapped at synaptic sites, NMDA receptors undergo constant cycling into and out of the postsynaptic density. Receptor movement is constrained by protein-protein interactions with both the intracellular and extracellular domains of the NMDAR. The role of extracellular interactions on the mobility of the NMDAR is poorly understood. Here we demonstrate that the positive surface charge of the hinge region of the N-terminal domain in the GluN1 subunit of the NMDAR is required to maintain NMDARs at dendritic spine …

A Crucial Role For The Protein Quality Control System In Motor Neuron Diseases., Riccardo Cristofani, Valeria Crippa, Maria Elena Cicardi, Barbara Tedesco, Veronica Ferrari, Marta Chierichetti, Elena Casarotto, Margherita Piccolella, Elio Messi, Mariarita Galbiati, Paola Rusmini, Angelo Poletti

Department of Neuroscience Faculty Papers

Motor neuron diseases (MNDs) are fatal diseases characterized by loss of motor neurons in the brain cortex, in the bulbar region, and/or in the anterior horns of the spinal cord. While generally sporadic, inherited forms linked to mutant genes encoding altered RNA/protein products have also been described. Several different mechanisms have been found altered or dysfunctional in MNDs, like the protein quality control (PQC) system. In this review, we will discuss how the PQC system is affected in two MNDs-spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS)-and how this affects the clearance of aberrantly folded proteins, which …

Understanding The Axonal Response To Injury By In Vivo Imaging In The Mouse Spinal Cord: A Tale Of Two Branches., Binhai Zheng, Ariana O Lorenzana, Le Ma

Department of Neuroscience Faculty Papers

Understanding the basic properties of how axons respond to injury in the mammalian central nervous system (CNS) is of fundamental value for developing strategies to promote neural repair. Axons possess complex morphologies with stereotypical branching patterns. However, current knowledge of the axonal response to injury gives little consideration to axonal branches, nor do strategies to promote axon regeneration. This article reviews evidence from in vivo spinal cord imaging that axonal branches markedly impact the degenerative and regenerative responses to injury. At a major bifurcation point, depending on whether one or both axonal branches are injured, neurons may choose either a …

Ephrin-B3 Controls Excitatory Synapse Density Through Cell-Cell Competition For Ephbs., Nathan T. Henderson, Sylvain J. Le Marchand, Martin Hruska, Simon Hippenmeyer, Liqun Luo, Matthew B. Dalva

Department of Neuroscience Faculty Papers

Cortical networks are characterized by sparse connectivity, with synapses found at only a subset of axo-dendritic contacts. Yet within these networks, neurons can exhibit high connection probabilities, suggesting that cell-intrinsic factors, not proximity, determine connectivity. Here, we identify ephrin-B3 (eB3) as a factor that determines synapse density by mediating a cell-cell competition that requires ephrin-B-EphB signaling. In a microisland culture system designed to isolate cell-cell competition, we find that eB3 determines winning and losing neurons in a contest for synapses. In a Mosaic Analysis with Double Markers (MADM) genetic mouse model system in vivo the relative levels of eB3 control …

The Tenets Of Teneurin: Conserved Mechanisms Regulate Diverse Developmental Processes In The Drosophila Nervous System, Alison T. Depew, Michael A. Aimino, Timothy J. Mosca

Department of Neuroscience Faculty Papers

To successfully integrate a neuron into a circuit, a myriad of developmental events must occur correctly and in the correct order. Neurons must be born and grow out toward a destination, responding to guidance cues to direct their path. Once arrived, each neuron must segregate to the correct sub-region before sorting through a milieu of incorrect partners to identify the correct partner with which they can connect. Finally, the neuron must make a synaptic connection with their correct partner; a connection that needs to be broadly maintained throughout the life of the animal while remaining responsive to modes of plasticity …

Propofol Inhibits The Voltage-Gated Sodium Channel Nachbac At Multiple Sites., Yali Wang, Elaine Yang, Marta M. Wells, Vasyl Bondarenko, Kellie Woll, Vincenzo Carnevale, Daniele Granata, Michael L. Klein, Roderic G. Eckenhoff, William P. Dailey, Manuel Covarrubias, Pei Tang, Yan Xu

Department of Neuroscience Faculty Papers

Voltage-gated sodium (Na_V) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic Na_V channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects …

Propofol Inhibits Prokaryotic Voltage-Gated Na+ Channels By Promoting Activation-Coupled Inactivation, Elaine Yang, Daniele Granata, Roderic G. Eckenhoff, Vincenzo Carnevale, Manuel Covarrubias

Department of Neuroscience Faculty Papers

Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na⁺ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations …

Map7 Regulates Axon Morphogenesis By Recruiting Kinesin-1 To Microtubules And Modulating Organelle Transport., Stephen R. Tymanskyj, Benjamin Yang, Kristen J. Verhey, Le Ma

Department of Neuroscience Faculty Papers

Neuronal cell morphogenesis depends on proper regulation of microtubule-based transport, but the underlying mechanisms are not well understood. Here, we report our study of MAP7, a unique microtubule-associated protein that interacts with both microtubules and the motor protein kinesin-1. Structure-function analysis in rat embryonic sensory neurons shows that the kinesin-1 interacting domain in MAP7 is required for axon and branch growth but not for branch formation. Also, two unique microtubule binding sites are found in MAP7 that have distinct dissociation kinetics and are both required for branch formation. Furthermore, MAP7 recruits kinesin-1 dynamically to microtubules, leading to alterations in organelle …

A-Type Kv Channels In Dorsal Root Ganglion Neurons: Diversity, Function, And Dysfunction, Benjamin M. Zemel, David M. Ritter, Manuel Covarrubias, Tanziyah Muqeem

Department of Neuroscience Faculty Papers

A-type voltage-gated potassium (Kv) channels are major regulators of neuronal excitability that have been mainly characterized in the central nervous system. By contrast, there is a paucity of knowledge about the molecular physiology of these Kv channels in the peripheral nervous system, including highly specialized and heterogenous dorsal root ganglion (DRG) neurons. Although all A-type Kv channels display pore-forming subunits with similar structural properties and fast inactivation, their voltage-, and time-dependent properties and modulation are significantly different. These differences ultimately determine distinct physiological roles of diverse A-type Kv channels, and how their dysfunction might contribute to neurological disorders. The importance …

Evolution Of Cortical Neurogenesis In Amniotes Controlled By Robo Signaling Levels., Adrián Cárdenas, Ana Villalba, Camino De Juan Romero, Esther Picó, Christina Kyrousi, Athanasia C Tzika, Marc Tessier-Lavigne, Le Ma, Micha Drukker, Silvia Cappello, Víctor Borrell

Department of Neuroscience Faculty Papers

Cerebral cortex size differs dramatically between reptiles, birds, and mammals, owing to developmental differences in neuron production. In mammals, signaling pathways regulating neurogenesis have been identified, but genetic differences behind their evolution across amniotes remain unknown. We show that direct neurogenesis from radial glia cells, with limited neuron production, dominates the avian, reptilian, and mammalian paleocortex, whereas in the evolutionarily recent mammalian neocortex, most neurogenesis is indirect via basal progenitors. Gain- and loss-of-function experiments in mouse, chick, and snake embryos and in human cerebral organoids demonstrate that high Slit/Robo and low Dll1 signaling, via Jag1 and Jag2, are necessary and …

Regional Microglia Are Transcriptionally Distinct But Similarly Exacerbate Neurodegeneration In A Culture Model Of Parkinson's Disease., Eric Wildon Kostuk, Jingli Cai, Lorraine Iacovitti

Department of Neuroscience Faculty Papers

BACKGROUND: Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SN) while neighboring ventral tegmental area (VTA) DA neurons are relatively spared. Mechanisms underlying the selective protection of the VTA and susceptibility of the SN are still mostly unknown. Here, we demonstrate the importance of balance between astrocytes and microglia in the susceptibility of SN DA neurons to the PD mimetic toxin 1-methyl-4-phenylpyridinium (MPP

METHODS: Previously established methods were used to isolate astrocytes and microglia from the cortex (CTX), SN, and VTA, as well as embryonic midbrain DA neurons from the …

Synaptic Nanomodules Underlie The Organization And Plasticity Of Spine Synapses., Martin Hruska, Nathan T. Henderson, Sylvain J. Le Marchand, Haani Jafri, Matthew B. Dalva

Department of Neuroscience Faculty Papers

Experience results in long-lasting changes in dendritic spine size, yet how the molecular architecture of the synapse responds to plasticity remains poorly understood. Here a combined approach of multicolor stimulated emission depletion microscopy (STED) and confocal imaging in rat and mouse demonstrates that structural plasticity is linked to the addition of unitary synaptic nanomodules to spines. Spine synapses in vivo and in vitro contain discrete and aligned subdiffraction modules of pre- and postsynaptic proteins whose number scales linearly with spine size. Live-cell time-lapse super-resolution imaging reveals that NMDA receptor-dependent increases in spine size are accompanied both by enhanced mobility of …

Representing Diversity In The Dish: Using Patient-Derived In Vitro Models To Recreate The Heterogeneity Of Neurological Disease, Layla T. Ghaffari, Alexander Starr, Andrew T. Nelson, Rita Sattler

Department of Neuroscience Faculty Papers

Neurological diseases, including dementias such as Alzheimer's disease (AD) and fronto-temporal dementia (FTD) and degenerative motor neuron diseases such as amyotrophic lateral sclerosis (ALS), are responsible for an increasing fraction of worldwide fatalities. Researching these heterogeneous diseases requires models that endogenously express the full array of genetic and epigenetic factors which may influence disease development in both familial and sporadic patients. Here, we discuss the two primary methods of developing patient-derived neurons and glia to model neurodegenerative disease: reprogramming somatic cells into induced pluripotent stem cells (iPSCs), which are differentiated into neurons or glial cells, or directly converting (DC) somatic …

Genome-Wide Profiling Reveals Functional Diversification Of ∆Fosb Gene Targets In The Hippocampus Of An Alzheimer's Disease Mouse Model., Jason C. You, Gabriel S. Stephens, Chia-Hsuan Fu, Xiaohong Zhang, Yin Liu, Jeannie Chin

Department of Neuroscience Faculty Papers

The activity-induced transcription factor ∆FosB has been implicated in Alzheimer's disease (AD) as a critical regulator of hippocampal function and cognition downstream of seizures and network hyperexcitability. With its long half-life (> 1 week), ∆FosB is well-poised to modulate hippocampal gene expression over extended periods of time, enabling effects to persist even during seizure-free periods. However, the transcriptional mechanisms by which ∆FosB regulates hippocampal function are poorly understood due to lack of identified hippocampal gene targets. To identify putative ∆FosB gene targets, we employed high-throughput sequencing of genomic DNA bound to ∆FosB after chromatin immunoprecipitation (ChIP-sequencing). We compared ChIP-sequencing results …

Epigenetic Suppression Of Hippocampal Calbindin-D28k By Δfosb Drives Seizure-Related Cognitive Deficits., Jason C. You, Kavitha Muralidharan, Jin W. Park, Iraklis Petrof, Mark S. Pyfer, Brian F. Corbett, John J. Lafrancois, Yi Zheng, Xiaohong Zhang, Carrie A. Mohila, Daniel Yoshor, Robert A. Rissman, Eric J. Nestler, Helen E. Scharfman, Jeannie Chin

Department of Neuroscience Faculty Papers

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. …