Pilot & Feasability Awards

2022 Awards
Autism as a Disorder of Synchronization of the Central and the Autonomic Nervous Systems

Investigator: Shlomit Beker,Ph.D.
Associate, Department of Pediatrics
Abstract

Autism Spectrum Disorder (ASD) is the most common form of neurodevelopmental disorder, affecting 1 in 44 individuals in the US alone. Despite intensive research, the mechanisms that underlie the cognitive atypicalities that characterize the disorder are not well understood.

Accumulating evidence from recent years point to altered synchronization of brain oscillations (central nervous system; CNS), and atypical regulation of body signals by the autonomic nervous system (ANS) in ASD. We hypothesize that the cognitive and behavioral rigidity35 that characterizes ASD result from altered modulation of CNS and ANS physiological activity by the environment. However, ANS synchronization with the environment, and the coordination between the ANS and CNS systems have not yet been tested in ASD. To address these significant gaps in knowledge, we propose to systematically test how CNS and ANS synchrony with the environment modulate perception and performance in social and non-social contexts in ASD. The proposed pilot study, and the research that will follow have the potential to get insight on novel mechanisms that could underlie the hallmark clinical deficits in ASD: 1) Cognitive and behavioral rigidity, defined in the DSM-V as restricted and repetitive patterns of behavior, interests or activities. 2) Altered social interaction, defined as Deficits in social communication and social interaction. In addition to a mechanistic framework for the hallmark phenotypes, a long-term goal of the proposed program of research is directed at translating the findings to establishing easy-to-deploy, noninvasive biomarkers that could provide indication for these phenotypes, against which intervention approaches can be developed.

Transcriptional programs regulated by the intellectual disability-associated histone demethylase KDM5C

Investigator: Julie Secombe, Ph.D.
Professor, Department of Genetics
Professor, Dominick P. Purpura Department of Neuroscience

Abstract
Variants in the gene encoding the transcriptional regulator KDM5C are found in patients with intellectual disability (ID). While the link between loss of function mutations in KDM5C and ID is clear, how KDM5C functions to mediate critical neuronal processes, and therefore the consequence of mutations for mechanisms of IDD, remains unknown. The goal of this proposal is to understand the relationship between KDM5C-regulated gene expression programs and the occurrence of ID. To do this, we will use iPSC-derived cerebral organoids, which recapitulate structural and molecular aspects of fetal brain development and are a critical research tool used to define the underlying cause(s) of neurodevelopmental disorders. We have generated iPSCs and organoids from two sources: (1) CRISPR-Cas9-generated KDM5C null alleles and (2) cells from a patient with KDM5C- induced ID caused by a missense change. These have been used to generate organoids alongside appropriate control cells, which we propose to characterize as part of this pilot project proposal.

Because organoids are comprised of distinct cell type, including excitatory and inhibitory neurons, we will use single cell RNA-seq (scRNA-seq) to decipher the transcriptional changes that occur at a single cell level. This will reveal changes to cellular differentiation programs and allow us to examine KDM5-regulated transcriptional programs in different cell types. This work is significantbecause we will define the etiological links between mutations in human KDM5C and ID. The proposed studies are innovativein the use of a new organoid model and use of the state-of-the-art genomics technique scRNA-seq.

Metabolomic profile of infantile spasms

Investigator: Aristea S Galanopoulou M.D., Ph.D.
Professor, The Saul R. Korey Department of Neurology (Pediatric Neurology)
Professor, Dominick P. Purpura Department of Neuroscience

ABSTRACT
Infantile epileptic spasms syndrome (IESS) is in infantile epileptic encephalopathy that manifests with epileptic spasms, often other types of epileptic seizures that evolve in a persisting drug-resistant epilepsy and intellectual disabilities. Its treatment options are distinct including hormonal therapies, vigabatrin, ketogenic diet. There is an urgent need to develop more effective treatments with disease modifying and antiepileptogenic effects. Our lab (Galanopoulou, Moshé) has optimized a model of drug-resistant IESS, the rat multiple-hit model, and has extensively used it to identify new treatments for IESS, including anti-inflammatory, anti-oxidative treatments, and mTOR inhibitors. Importantly, we have recently published that a pulse 3-day rapamycin treatment, starting after spasms onset, can stop spasms, ameliorate learning and memory and significantly reduce the epilepsy incidence in adulthood.

Our preclinical data in the model as well as clinical data on metabolic etiologies of ISS and efficacy of treatments such as ketogenic diet in ISS strongly implicate a role of metabolic dysfunction in the pathogenesis and treatments of IESS. Therefore, we propose to collaborate with Dr Irwin Kurland, director of the stable isotope and metabolomics core facility of the Einstein diabetes research center, to determine the metabolomic signatures associated with IESS in the multiple-hit rat model of ISS as well as treatment response to a disease-modifying, antiepileptogenic treatment for spasms, such as rapamycin. This proposal is expected to provide insights on metabolic pathways that are dysregulated in IESS and are reversed by disease-modifying treatments, which will be guiding future studies to develop more effective treatment strategies for IESS.

Testing computational theories of visual processing in ASD with a novel integrated approach

Investigator: Ruben Coen-Cagli
Associate Professor, Department of Systems & Computational Biology
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Ophthalmology & Visual Sciences

Abstract
Sensory processing has become a central focus of autism spectrum disorder (ASD) research for several reasons. Differences in sensory traits in autism are visible early during development, are predictive of diagnosis later in life, and also correlate with social and cognitive impairments. Therefore, sensory traits could provide reliable and fine-grained diagnostic criteria. Characterizing low-level sensory processing can also provide insights into general neural computations that may be disrupted in ASD. Those insights would help draw a bridge between difficulties in sensory processing and other behavioral domains. Lastly, it is relatively easy to translate sensory behavioral findings between humans and animal models, which allows testing neural circuit motifs that may be affected in ASD. A crucial part of this progress has been the development of computational theories to explain empirical observations and behavioral deficits. However we lack a framework to unify disparate observations, compare alternative theories quantitatively, and generate new predictions that can be tested experimentally. To overcome this barrier, we will use a novel integrated experimental and computational approach we developed recently to study how visual sensory information is integrated across space and over time in perceptual grouping and segmentation (pGS). In collaboration with the Cognitive Neurophysiology Laboratory, we will collect and analyze new datasets in high-functioning ASD participants and controls with matched age and IQ. We will test the hypothesis that probabilistic inference for pGS predicts when and how disrupted static and dynamic contextual integration in ASD leads to impaired estimation and updating of uncertainty.

Investigating the role of hilar mossy cells of the hippocampus in Fragile X Syndrome

Investigator: Coralie Berthoux, Ph.D.
Associate, Dominick P. Purpura Department of Neuroscience

ABSTRACT
Loss of Fragile X messenger ribonucleoprotein 1 (FMRP) causes Fragile X Syndrome (FXS), which is the leading monogenetic cause for cognitive impairments. FXS is characterized by attention deficits, intellectual disabilities, stereotypic behavior, and epilepsy. While FMRP has been described to play a major role in synaptic function, how FMRP loss leads to synaptic and circuit defects in FXS remains poorly understood. In the dentate gyrus (DG), a key brain area involved in memory formation and epilepsy, granule cells (GCs) and hilar mossy cells (MCs) establish a recurrent GC-MC-GC excitatory loop. We recently reported that MC-GC synapses undergo a mechanistically novel, NMDA receptor-independent form of long-term potentiation (MC-GC LTP) whose induction requires postsynaptic BDNF/TrkB signaling. By increasing the excitation/inhibition (E/I) balance, MC- GC LTP enhances GC output, thereby facilitating activation of the GC-MC-GC recurrent circuit. Preliminary results indicate that Fmr1 deletion is associated with MC-GC synaptic strengthening, but the mechanisms and functional relevance are unclear. In addition, the endocannabinoid system, a powerful regulator of the MC-GC synapse, is dysregulated in FXS. We hypothesized that abnormal strengthening of MC-GC transmission in FXS, by disrupting the E/I balance, significantly contribute to cognitive deficits and seizure susceptibility. By combining complementary approaches, we will explore the molecular and cellular mechanisms underlying activity-dependent plasticity at MC-GC synapse in physiological conditions, as well as in FXS. By studying dysregulation of activity-dependent synaptic plasticity in FXS, the proposed studies may not only unravel novel mechanisms underlying this disorder, but also facilitate the development of novel therapeutic strategies.

2021 Awards
Translational studies in an iPSC model of Jansen DeVries Syndrome (JDVS).

Investigator: Herbert M. Lachman, M.D.
Professor, Department of Psychiatry and Behavioral Sciences

Abstract for Translational studies in an iPSC model of Jansen DeVries Syndrome (JDVS).
We have established the first iPSC model for Jansen-de Vries Syndrome (JDVS), which is caused by de novo nonsense or frameshift mutations in PPM1D exons 5 and 6 resulting in translation of a truncated protein. JDVS is characterized by IDD, gastrointestinal problems, food avoidance, high pain threshold, autism spectrum disorder (ASD) and psychiatric problems. PPM1D codes for a phosphatase that negatively regulates p53 and other members of the DNA repair pathway. PPM1D can also affect neuronal function by, in part, dephosphorylating regulators of neurite outgrowth and synaptic function, such as p38 MAPK and CaMK2. Gain-of-function mutations in PPM1D have been found in numerous cancers suggesting that the gene acts as a tumor suppressor through excessive dephosphoryation and inactivation of proteins involved in DNA repair. Among the gain-of-function somatic mutations found in various cancers are the same truncating variants in exon 5 and 6 identified in JDVS. In cancer cells, these mutations lead to an increase in phosphatase activity by stabilizing the catalytic domain (encoded by exons 1-4). Preliminary RNA-seq and phosphoproteomics experiments carried out on JDVS and control glutamatergic neurons, and cerebral organoids, support a gainof-function effect and predict widespread effects on cytoskeletal proteins, neurite outgrowth, synaptic function, neuropeptide signaling, and chromatin structure. In this pilot project, we propose to carry out functional studies to validate the OMICS findings and determine whether PPM1D inhibitors can rescue neuronal molecular and cellular phenotypes caused by JDVS mutations, a critical first step in translating basic research findings to clinical use.

Cellular, molecular and pharmacological studies in a mouse model of Pol III-related Leukodystrophy

Investigator: Ian M. Willis, Ph.D.
Professor, Department of Biochemistry

Abstract for Cellular, molecular and pharmacological studies in a mouse model of Pol III-related Leukodystrophy
RNA polymerase (Pol) III-related leukodystrophy is a recently identified autosomal recessive neurodegenerative disorder that causes hypomyelination with variable disease onset and severity. Based on the frequency of disease-causing alleles in genomic databases, Pol III-related leukodystrophy is predicted to be the second most prevalent leukodystrophy. Patients typically present during childhood with neurological deficits that include developmental delay, cognitive regression, motor impairment and intellectual disability. Additional clinical characteristics can include myopia, hypodontia, short stature and hypogonadotropic hypogonadism, among others. An understanding of disease mechanisms is currently lacking and treatments are limited to palliative care. Recently, an Olig2 lineage-specific knock-in mouse model of Pol III-related leukodystrophy has been developed that exhibits features of the disease seen in patients. These include reduced growth and developmental delay, deficits in cognitive, sensory and fine sensorimotor function, and hypomyelination in multiple regions of the cerebrum and spinal cord. Disease pathogenesis in the mice involves defects that reduce both the number of mature myelinating oligodendrocytes and the ability of these cells to produce a myelin sheath of normal thickness. The findings to date highlight the sensitivity of oligodendrogenesis and myelination to perturbations of Pol III transcription. However, the cellular and molecular mechanisms of pathogenesis remain poorly characterized. To advance understanding in this area we will use single cell RNA sequencing to investigate how the heterogeneity of the oligodendrocyte cell population has been impacted in the cerebrum of Pol III leukodystrophic mice. We will also test a pharmacological approach to promote oligodendrogenesis in this hypomyelinating disease model.

Role of Tet enzymes and 5hmC in neurodevelopment and neuronal function.

Investigator: Meelad M. Dawlaty, Ph.D.
Associate Professor, Department of Genetics

Abstract for Role of Tet enzymes and 5hmC in neurodevelopment and neuronal function.
Brain development and function are regulated by epigenetic mechanisms involving DNA methylation and demethylation. DNA methylation (5mC) is a modification in DNA that silences genes. DNA is methylated by DNA methyltransferases (Dnmts) and demethylated by dioxygenases Tet1, Tet2 and Tet3. Tet enzymes convert 5mC to 5-hydroxymethylcytosine (5hmC) and other oxidized products leading to removal of the methyl group. Tet enzymes and 5hmC are abundant in many brain cell types. 5hmC levels increase during neurogenesis and over adult lifespan in the brain. Mutations and deregulation of Tet genes as well as abnormal neuronal 5hmC content/landscape is documented in selected craniofacial/neurological syndromes that are accompanied with intellectual and developmental disabilities (IDDs). However, to date the role of Tet enzymes and 5hmC in neurogenesis and brain function is poorly defined, hampering our understanding of their causal roles in etiology of IDDs. We hypothesize that Tet enzymes are essential for proper establishment of 5hmC landscape, DNA demethylation, and activation of neuro-developmental and neuronal genes. Their loss compromises proper neurogenesis and neuronal activity with implications for IDD. We propose two aims. Aim one will establish the roles of Tets/5hmC in NSC self-renewal and multipotency during neurogenesis. Aim two will define the roles of Tets/5hmC in neuronal activity and cognition. Our findings will establish Tets/5hmC as regulators of gene expression critical for NSC biology, neurogenesis, and neuronal activity with implications in IDDs. Since epigenetic modifications are reversible, Tets/5mC/5hmC levels may serve as therapeutic targets for treatment of IDDs and/or as diagnostic biomarkers.

Developmental Dysfunction of Parvalbumin Interneurons in Neurodevelopmental Disorders.

Investigator: Renata A. Batista-Brito, Ph.D.
Assistant Professor, Dominick P. Purpura Department of Neuroscience

Abstract for Developmental Dysfunction of Parvalbumin Interneurons in Neurodevelopmental Disorders
Small de novo deletions in the Mef2c locus, as well as missense mutations, have been reported in several patients with neurodevelopmental disorders (NDDS) such as intellectual disability and autism spectrum disorders (ASD). Mef2c is a transcription factor that plays a role in several cortical developmental processes including neuronal migration, survival, differentiation, and synaptic function. Mef2c also regulates various other NDDs susceptibility genes. Mice missing one copy of Mef2c (Mef2c-haploinsufficiency model) exhibit behavioral deficits resembling those of human patients with Mef2c deficiency rare disorder, including deficits in social interactions and repetitive behaviors. At a cortical level, these animals have altered neurotransmission, however the relationship between Mef2c signaling and neural dysfunction remains unknown. Mef2c is expressed in excitatory neurons and a subset of inhibitory interneurons that express parvalbumin (PV-INs). Loss of Mef2c in excitatory neurons recapitulates some, but not all the phenotypes observed in the Mef2c-haploinsufficiency model, strongly suggesting that Mef2c signaling in PV-INs plays a major role in Mef2c related phenotypes. However, nothing is known about how Mef2c impacts the development of PV-INs. Here we will test the hypothesis that Mef2c is essential for PV-IN synaptic development and that loss of Mef2c in PV-Ins leads to NDD-related endophenotypes. This project has the potential to improve the lives of children with rare mutations and intellectual disabilities. Mef2c is a rare disease gene for which very little in know about. In humans Mef2c mutations leads to alterations in brain development and results in intellectual disability. We propose to do a pilot study to address the developmental consequences resulting from loss of Mef2c in PV-INs, the main keepers of inhibition.

Investigating the impact of perinatal events on circuit development in the Cerebellum

Investigator: Stephanie Rudolph, Ph.D.
Assistant Professor, Dominick P. Purpura Department of Neuroscience

Abstract for Investigating the impact of perinatal events on circuit development in the Cerebellum
Perinatal events, such as complications during labor, delivery mode, maternal infection, stress and mother-infant interactions are thought to affect neurodevelopment. It has been hypothesized that the brain is exposed to many maternal and fetal neuromodulators like oxytocin and vasopressin during this time window, and that these neuromodulators orchestrate neuronal maturation and circuit assembly. In consequence, disruption of these signals can impede normal brain development, leading to cognitive impairment and behavioral abnormalities consistent with neurodevelopmental disorders like autism spectrum disorders (ASD) and attention deficit/hyperactivity disorder (ADHD). These disorders are often associated with cerebellar pathology in humans. In addition, dysfunction of the principal neurons of the cerebellar cortex, the Purkinje cells, is associated with autism-like behavioral deficits in mice. However, it remains unclear how perinatal events influence cerebellar development and related pathologies. While single cell RNA sequencing revealed that oxytocin receptors (OTRs) are absent in the adult cerebellum, cerebellar progenitors transiently express OTRs during development, suggesting that cerebellar progenitors might be sensitive to neuropeptides released during the perinatal time period. Using a combination of mouse genetics, histology, electrophysiology and behavioral testing, I propose to examine whether OTR and related vasopressin receptor (AVPR) signaling during development is crucial for establishing the cerebellar circuit, and whether genetic disruption or manipulations that interfere with OTR and AVPR signaling in the developing brain contribute to cerebellar circuit malformation and behavioral abnormalities associated with ASD and ADHD.

2020 Awards
Regulation of the Cytoplasmic Dynein-Dynactin Motor Complex by Lis1

Investigator: Arne Gennerich, Ph.D.
Professor, Department of Biochemistry

Abstract for Regulation of the Cytoplasmic Dynein-Dynactin Motor Complex by Lis1
The microtubule motor cytoplasmic dynein, in cooperation with its regulatory proteins, drives several processes essential to embryonic development, including neuronal proliferation, neuronal migration, and the transport of numerous intracellular cargoes. Thus, it is not surprising dysfunction of dynein contributes to birth defects. A striking example is lissencephaly (LIS), a rare, but devastating brain malformation. Variants of the disease are caused by loss or mutation of the dynein regulator Lis1. In LIS, neurons fail to migrate properly during development. Affected infants’ brains lack the normal gyral folding pattern and layering of the cerebral cortex. These children suffer untreatable epilepsy and severe psychomotor retardation, often dying in the first year of life. Unfortunately, mechanistic insights into dynein function and its regulation by Lis1 are limited, hampering our ability to understand the molecular basis for LIS and other dynein-linked human diseases. In this proposal, we will combine single-molecule fluorescence and optical tweezers-based force measurements with innovative protein engineering to determine how cytoplasmic dynein together with its activator, dynactin, is regulated by Lis1. We will decipher how Lis1 regulates the motion and force generation of dynein-dynactin, and determine the effects of human disease mutations on dynein-dynactin-Lis1 function. These studies will provide a new understanding of dynein-linked diseases, and elucidate molecular targets for future therapeutic interventions.

COL4a1 mutants and the astrocyte endfoot and endothelial junctions

Investigator: David C. Spray, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience

Abstract for COL4a1 mutants and the astrocyte endfoot and endothelial junctions
COL4a1 encodes an isoform of Collagen 4, which is a major component of the basement membrane separating endothelial cells from astrocytes on brain vasculature. Prominent neural phenotypes of patients with COL4a1 mutations are defects in vessel development and fragility, reflected in infarcts, deep brain edema, migraine, etc. Disease-casing COL4a1 mutations appear to target binding domains, and are associated with endothelial cell detachment. We hypothesize that these disorders may primarily target the neurovascular unit (NVU), the interface between endothelial cells and astrocytes that constitutes the blood-brain-barrier (BBB). A year ago we applied for and were awarded a pilot project to test this hypothesis, using novel in vitro models of the NVU to measure BBB tightness, determining co-localization of COL4a1 and cellular binding partners and determine affinities between COL4a1 and molecular receptors. For this we generated viral vectors with WT and disease-causing COL4a1 variants and are using them to evaluate binding of endothelial cells and astrocytes to basement membrane components. We have also had the opportunity to meet with patient with the Col4a1 mutation that we are studying and her parents. We have also recently established a collaboration with the laboratory of Doug Gould at UCSF, who has generated mouse Col4a1 mutants at analogous sites to those of our viral constructs; those mice exhibit apparent brain vascular anomalies but the brain microvasculature has not been characterized in detail. We are currently using confocal microscopy and.super-resolution microscopy to examine astrocyte endfeet and endothelial junctional complexes in brains of those mice. This proposal is for funding to support that research and to allow the generation of a mouse by our Gene Targeting Core with the mutation corresponding to that of the Operation Gene Team patient. Such a model will enable further study of functional and behavioral phenotype and will also allow testing potential therapeutic interventions. With the mouse model and with the microscopy data, we believe that we will be able to write a competitive proposal for NIH funding.

Mapping the neural cell type expression of ASD and IDD associated genes

Investigator: Deyou Zheng, Ph.D.
Professor, The Saul R. Korey Department of Neurology

Abstract for Mapping the neural cell type expression of ASD and IDD associated genes
Genetics studies including whole genome and whole exome sequencing have identified a few hundreds of genes associated with autism spectrum disorder (ASD) and other intellectual developmental disability (IDD). While these genetic studies have shed critical insights to the genetic complexity of the IDD, we need to follow up the findings by functional studies using animal or human cell models. A key question in developing an effective model is what kind of neural or brain cell type to target. This is what the current pilot project plans to address. We hypothesize that the cell types in which a candidate gene is highly expressed are the most important cells to be affected by functional mutations in this gene. Accordingly, we plan to apply our bioinformatics expertise to perform integrative analysis of single cell RNA-seq (scRNA-seq) data that have just become available in recent few years. We will collect brain and neural datasets from public sources and recent scRNA-seq studies to build a comprehensive single cell expression map of ASD and IDD associated genes. Our main goal is to build a community resource for our IDDRC investigators to develop innovative projects to study the molecular and cellular functions of IDD and ASD candidate genes. The two aims are, 1) using publicly available scRNA-seq data to build a comprehensive expression atlas of all ASD/IDD-associated genes, and 2) performing gene co-expression analysis to build an ASD/IDD gene co-expression network. Completion of these aims will organize IDD/ASD-associated genes into distinct expression categories and recommend the cell types to target for functional studies of each candidate gene. This pilot project is highly relevant to IDD and the mission of the IDDRC as it will generate a valuable bioinformatics resource for functional studies of genes associated to ASD and other IDDs.

COL4a1 mutants and the astrocyte endfoot and endothelial junctions

Investigator: Peri Kurshan, Ph.D.
Assistant Professor, Dominick P. Purpura Department of Neuroscience

Abstract for COL4a1 mutants and the astrocyte endfoot and endothelial junctions
Intellectual disability (ID) affect approximately 1-3% of the US population. Defects in synapse development and function have been shown to be a hallmark of disorders characterized by ID, and human genetic studies have begun to shed light on the synaptic genes implicated. Calcium channels encoded by the CACNA1A gene in mammals have recently been linked to ID. We have recently shown that the Autism-susceptibility gene neurexin, which encodes a synaptic cell adhesion molecule, serves to cluster calcium channels at the presynaptic active zone. We went on to show that, surprisingly, neurexin’s function is mediated by its intracellular domain rather than its well-studied extracellular binding domains. Here we are proposing to determine the mechanism by which neurexin functions to organize presynaptic calcium channels, as well as to identify additional novel mediators of calcium channel localization. Finally, we will generate transgenic animals containing a CACNA1A genetic lesion recently identified in an IDDRC patient in order to characterize the effects of that mutation. We use C. elegans as a model system and a tool for gene discovery because of its conserved molecular and cellular processes within a simplified genome and nervous system, as well as the powerful genetic and imaging tools at our disposal. The goal of our project is to identify conserved mechanisms by which calcium channels are clustered at sites of vesicle release, that might be useful therapeutic targets for disorders characterized by calcium channel dysfunction.

Temporal regulation of activity-regulated gene expression in hippocampal neurons by histone modifications

Investigator: Sulagna Das, Ph.D.
Research Assistant Professor, Department of Cell Biology

Abstract for Temporal regulation of activity-regulated gene expression in hippocampal neurons by histone modifications
Deficits in learning and memory are hallmarks of several intellectual and neurodevelopmental disorders. These cognitive processes in both normal and disease states are controlled by spatiotemporally regulated genes in neuronal circuits. Studies on how and which genes influence such cognitive function/behavior have implicated the role of immediate-early genes (IEGs), particularly, Activity-regulated cytoskeletal associated (Arc/Arg3.1). Arc has garnered special interest because it affects synaptic transmission, plasticity and long-term memory and has been implicated in autism, various neurodevelopmental and mood disorders. However, it is still unknown how Arc levels are maintained over time to ensure long-term consolidation. For IEGs including Arc, the regulation of gene expression initiates at the level of transcription. Our preliminary data using a knock-in mouse where the endogenous Arc gene is labeled have shown cycles of Arc transcription in a subset of neurons may contribute to maintaining mRNA levels over time scales of consolidation. However, the molecular regulation of this process and the associated changes in the chromatin landscape which primes for self-perpetuating cycles of Arc transcription is unknown. The goal of the project will be to identify the histone modifications on Arc and other IEGs by ChIP sequencing and identify the precise “histone code” during the different temporal phases of Arc transcription. This is particularly relevant for IEGs like Arc which have a tightly controlled window of expression with precise ON-OFF kinetics. We hypothesize that altering the precise histone code would lead to aberrant changes in methylation and acetylation of Arc. This may be responsible for dysregulated transcriptional patterns, resulting is less efficient learning and cognitive performance- characteristic features of IDD. By determining the temporal regulation of enzymatic activity of GATAD2B, we expect to provide molecular insights into how mutations in these enzymes affect synaptic plasticity and in turn complex cognitive functions

2019 Awards
Small molecule inhibition of ganglioside synthesis as potential therapy for free sialic acid storage disease.

Investigator: Kostantin Dobrenis, Ph.D.
Assistant Professor, Dominick P. Purpura Department of Neuroscience

Molecular dysfunction of cytoplasmic dynein in brain developmental diseases

Investigator: Arne Gennerich, Ph.D.
Associate Professor, Department of Anatomy & Structural Biology

Modeling CACNA1A-associated intellectual disability using human cerebellar neurons derived from induced pluripotent stem cells

Investigator: Herbert M. Lachman M.D., Ph.D.
Professor, Department of Psychiatry and Behavioral Sciences
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Genetics
Investigator: Deyou Zheng, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Genetics
Professor, The Saul R. Korey Department of Neurology

DYNC1H1 mutant in zebrafish-to model a human phenotype

Investigator: Bridget Shafit-Zagardo, Ph.D.
Professor, Department of Pathology
Investigator:  Teresa Bowman, Ph.D.
Professor, Department of Developmental & Molecular Biology

Impact of COL4A1 mutations on function and remodeling of the neurovascular unit

Investigator: David Spray, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Medicine (Cardiology)

2018 Awards
The role of Fragile X mental retardation protein in presynaptic protein synthesis and plasticity

Investigator: Pablo Castillo, M.D., Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Psychiatry Behavioral Sciences
Harold and Muriel Block Chair in Neuroscience

Crk and Crkl mutations as causes for epilepsy in IDD

Investigator: Aristea Galanapoulou M.D., Ph.D.
Professor, The Saul R. Korey Department of Neurology (Child Neurology)
Professor, Dominick P. Purpura Department of Neuroscience
Investigator: Jean M. Hebert Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Genetics

Modeling the neuropsychiatric manifestations of Lowe Syndrome using induced pluripotent stem cells

Investigator: Herbert M. Lachman M.D., Ph.D.
Professor, Department of Psychiatry and Behavioral Sciences
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Genetics
Investigator: Deyou Zheng, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Genetics
Professor, The Saul R. Korey Department of Neurology

Studies on Pol III-Associated Leukodystophy

Investigator: Ian M. Willis, Ph.D.
Professor, Department of Biochemistry
Professor, Department of Systems & Computational Biology

Converging mechanisms in Autism Spectrum Disorder

Investigator: Bryen Jordan, Ph.D.
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Psychiatry Behavioral Sciences

2017 Awards
Binding studies of neural cell adhesion proteins

Investigator: Steve Almo, Ph.D.
Chair, Department of Biochemistry
Wollowick Family Foundation Chair in Multiple Sclerosis & Immunology
Director, Einstein Macromolecular Therapeutics Development Facility
Professor, Department of Biochemistry
Professor, Department of Physiology & Biophysics

Investigator: Scott Emmons, Ph.D.
Siegfried Ullmann Chair, Molecular Genetics
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Genetics

Exploring nAChR Function in Fragile X Syndrome

Investigator: Anna Francesconi, Ph.D.
Assistant Professor, Developmental Medicine

Converging mechanisms in Autism Spectrum Disorder

Investigator: Bryen Jordan, Ph.D.
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Psychiatry Behavioral Sciences

Whole exome sequence analysis of ID in patients with 22q11.2DS

Investigator: Bernice Morrow, Ph.D.
Sidney L. and Miriam K. Olson Chair in Cardiology
Director, Division of Translational Genetics, Department of Genetics
Professor, Department of Genetics
Professor, Department of Obstetrics & Gynecology and Women's Health
Professor, Department of Pediatrics (Pediatric Cardiology)

Cerebellar hypoplasia and saccadic adaptation in Autism Spectrum Disorder

Investigator: Lars Ross, Ph.D.
Assistant Professor, Developmental Medicine

Autophagy as a new therapeutic target for cognitive defects in Fragile X Syndrome

Investigator: Suzanne Zukin, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Director, Neuropsychopharmacology Center
F.M. Kirby Chair in Neural Repair and Protection

2016 Awards
The neurophysiological underpinnings of sensory-motor dysfunctions in autism spectrum disorder

Investigator: Pierfilippo De Sanctis, Ph.D.
Research Assistant Professor, Department of Pediatrics (Developmental Medicine)
Research Assistant Professor, The Saul Korey Department of Neurology

MECP2 and 5-hydroxymethylcytosine in epigenetic regulation of neuronal gene expression and etiology of Rett Syndrome

Investigator: Meelad Dawlaty, Ph.D.
Assistant Professor, Department of Genetics

Identification of novel pathogenic pathways and therapeutic targets in CNS of lysosomal storage disease

Investigator: Kostantin Dobrenis, Ph.D.
Assistant Professor, Dominick P. Purpura Department of Neuroscience

Protection against hearing loss with Cyclodextrin treatment of Niemann-Pick Type C Disease

Investigator: Vytautas Verselis, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience

Uncovering the molecular link between CHD8 and ASD

Investigator: Deyou Zheng, Ph.D.
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Genetics
Associate Professor, The Saul Korey Department of Neurology

2015 Awards
Learning during an early sensitive period in chickens

Investigator:
Jose Pena, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience

Elucidation of the mechanism of trinucleotide repeat instability in patient cells

Investigator:
Jeannine Gerhardt, Ph.D.
Instructor, Department of Cell Biology

Primary microglial dysfunction in a subset of ASD

Investigator:
Herb Lachman, M.D.
Professor, Department of Psychiatry and Behavioral Sciences
Professor, Department of Medicine (Hematology)
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Genetics

Is increased surface CCR2 on mature monocytes from perinatally HIV infected and perinatally HIV exposed children a biomarker of neurocognitive impairment?

Investigators:
Joan Berman, Ph.D.
Professor, Department of Pathology
Professor, Department of Microbiology & Immunology
Professor, Department of Microbiology & Immunology
Senior Academic Advisor to the Graduate Division

Kami Kim, M.D.
Professor, Department of Medicine (Infectious Diseases)
Professor, Department of Microbiology & Immunology
Professor, Department of Pathology

Biomarkers to predict neurodevelopmental outcomes in very preterm infants

Investigators:
Mamta Fuloria, M.B., B.S.
Assistant Professor, Department of Pediatrics (Neonatology)

Maureen J. Charon, Ph.D.
Professor, Department of Biochemistry
Professor, Department of Obstetrics and Gynecology and Woman’s Health
Professor, Department of Medicine

William A. Gomes, M.D., Ph.D.
Assistant Professor, Department of Radiology (Neuroradiology)

Genetics causes of intellectual disability in 22q11DS patients

Investigator: Tingwei Guo, Ph.D.
Research Assistant Professor, Department of Genetics

Dynamic live cell single molecule imaging of MeCP2 mutants linked to neurological disorders

Investigator:
Robert Coleman, Ph.D.
Assistant Professor, Department of Anatomy and Structural Biology

MeCP2, mRNA, gap junctions and glia

Investigators:
David C. Spray, Ph.D.
Professor of Neuroscience and Medicine

Randy Stout, Ph.D.
Research Fellow

2014 Awards
Establishing an in vivo high-density electrophysiological methodology to interrogate circuit-level functional connectivity in genetic mouse models of autism

Investigators:
John Foxe, Ph.D.
Professor, Department of Pediatrics
Professor, Dominick P. Purpura Department of Neuroscience
Noboru Hiroi, Ph.D.
Professor, Department of Psychiatry and Behavioral Sciences
Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Genetics

Impaired inter-hemispheric communication, information processing differences, executive function deficits, and network communication in ASD

Investigator: Sophie Molholm, Ph.D.
Associate Professor, Dominick P. Purpura Department of Neuroscience
Associate Professor, Department of Pediatrics

Adverse Childhood Experiences (ACEs)

Investigator: Anne Murphy, Ph.D.
Assistant Professor, Department of Pediatrics (Child Development)

Characterization of Slc9a6 and Slc9a9 KO mice and their relationship to neurogenetic disease

Investigator: Steven Walkley, D.V.M., Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Professor, Department of Pathology
Professor, The Saul R. Korey Department of Neurology
Director, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center

The mammalian target of rapamycin complex 2 (mTORC2) as a critical regulator of synaptic defects in Fragile X Syndrome

Investigator: Suzanne Zukin, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience
Director, Neuropsychopharmacology Center
F.M. Kirby Chair in Neural Repair and Protection

Functional Brain Mechanisms of Inattention in Children with ASD and ADHD

Investigator: Xiaobo Li, Ph.D.
Assistant Professor, Department of Radiology
Assistant Professor, Dominick P Purpura Department of Neuroscience
Assistant Professor, Department of Psychiatry and Behavioral Sciences

2013 Awards
Epigenetic regulation by MeCP2 and its role in neuronal diseases

Investigator: Michael Brenowitz, Ph.D.
Professor, Department of Biochemistry

Synaptic connectivity using three mouse models of ASD

Investigator: Pablo Castillo, Ph.D.
Professor, Dominick P. Purpura Department of Neuroscience

Automated quantification of motor stereotypies in children with Autism Spectrum Disorders

Investigator: Sylvie Goldman, Ph.D.
Instructor, The Saul R. Korey Department of Neurology and Department of Pediatrics

Exploring a role for AIDA-1 in Schizophrenia and Autism Spectrum Disorders

Investigator: Bryen Jordan, Ph.D.
Assistant Professor, Dominick P. Purpura Department of Neuroscience
Assistant Professor, Department of Psychiatry and Behavioral Sciences

The TWEAK/Fn14 pathway in the pathogenesis and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE)

Investigator: Chaim Putterman, M.D.
Professor, Department of Medicine
Professor, Department of Microbiology & Immunology

Intellectual disability caused by mutations in KDM5C

Investigator: Julie Secombe, Ph.D.
Assistant Professor, Department of Genetics

2012 Awards
Saturday, March 5th, 2012

Dr. Catherine Lord
From 2 to 22: As the number of preschool children identified with Autism Spectrum Disorder (ASD) increases each year, so too will the number of children with ASD moving

Monday, December 17, 2012

Brett Abrahams, Ph.D.
Assistant Professor, Department of Genetics
Albert Einstein College of Medicine
Combined Clinical and Molecular Genetics Conference
Topic: Structural variation at 15q11.2

Monday, December 10, 2012

Tong Sheng
Doctoral Candidate
Brain and Creativity Institute
Neuroscience Graduate Program
University of Southern California
Task-specific network-level representations of human vocal emotions

Thursday, December 6, 2012

First Annual Isabelle Rapin Conference on Communicable Disorders
WILLIAMS SYNDROME WORKSHOP AND ROUNDTABLE

Tuesday, December 4, 2012

David J. Lewkowicz, Ph.D.
Professor
Department of Psychology and Center for Complex Systems & Brain Sciences
Florida Atlantic University
The Critical Role of Experience in the Acquisition of Knowledge in Human Infants

Monday, December 3, 2012

Yuliya Yoncheva, Ph.D.
Postdoctoral Fellow
Department of Psychology and Human Development
Peabody College, Vanderbilt University
Brain correlates of selective attention to language: implications for reading acquisition

Wednesday, November 21, 2012

Ian Robertson, Ph.D.
Visiting Professor of Neurology at Columbia University, New York
Professor of Psychology at Trinity College Dublin, Ireland
Why education and mental stimulation protect the brain: The role of noradrenaline in cognitive reserve

Monday, November 19, 2012

Bernice Morrow, Ph.D.
Professor, Departments of Genetics, Obstetrics & Gynecology and Women's Health, and Pediatrics
Director, Division of Translational Genetics, Department of Genetics
Sidney L. and Miriam K. Olson Chair in Cardiology
Albert Einstein College of Medicine
Susan Klugman, M.D.
Clinical Genetics, Obstetrics & Gynecology
Montefiore Medical Center
Associate Professor of Clinical Obstetrics & Gynecology and Women's Health
Albert Einstein College of Medicine
Combined Clinical and Molecular Genetics Conference
Topic: Highlights from the 2012 American Society of Human Genetics Meeting

Saturday, November 17, 2012

B.R.A.I.N. Kids!

Thursday, November 1, 2012

Aristea Galanopoulou, M.D., Ph.D.
Associate Professor, Department of Neurology
Associate Professor, Department of Neuroscience
Albert Einstein College of Medicine
Modeling new therapies for infantile spasms, lessons from animal models

Monday, October 15, 2012

Bernice Morrow, Ph.D.
Professor, Departments of Genetics, Obstetrics & Gynecology and Women's Health, and Pediatrics
Director, Division of Translational Genetics, Department of Genetics
Sidney L. and Miriam K. Olson Chair in Cardiology
Albert Einstein College of Medicine
Combined Clinical and Molecular Genetics Conference
Topic: 22q11.2 Deletion Syndrome

Thursday, October 4, 2012

Brett Abrahams, Ph.D.
Assistant Professor, Department of Genetics
Albert Einstein College of Medicine
Integrative Approaches to the Autism Spectrum Disorder: from molecules to behaviors

Wednesday, September 26, 2012

Christopher Brett, Ph.D.
Assistant Professor and Canada Research Chair
Biology Department, Concordia University
Christianson syndrome, ADHD and NHEs: How sodium/hydrogen exchangers control neuronal endocytosis and their relationship to disease

Monday, September 24, 2012

Aleksandra Djukic, M.D., Ph.D.
Associate Professor of Clinical Neurology and Pediatrics
Director of the Center for Rett Syndrome
Albert Einstein College of Medicine and Montefiore Medical Center
Combined Clinical and Molecular Genetics Conference
Topic: Rett Syndrome

Wednesday, July 18, 2012

Daniel Senkowski, Ph.D.
Professor of Clinical Neuropsychology, Multisensory Integration Research Group
Department of Psychiatry and Psychotherapy, Charité, University Medicine Berlin, Germany
Crossmodal biasing of pain

Monday, July 16, 2012

Curtis Deutsch, Ph.D.
Associate Professor, Department of Psychiatry, UMMS
Director, Craniofacial Research Program and Psychobiology Program, Eunice Kennedy Shriver Center UMMS
Mclean Hospital, Harvard Medical School
Craniofacial and brain dysmorphology in autism and schizophrenia

Friday, July 6, 2012

Manuel Garcia-Garcia, Ph.D.
Postdoctoral Fellow, Phyllis Green and Randolph Cowen Institute for Pediatric Research, NYU Child Study Center, New York
Intra-individual stability of resting-state functional networks: a new reliable tool shows functional segregation of the basal ganglia in ADHD

Monday, May 21, 2012

Rick Kaskel, M.D., Ph.D.
Chief of the Division of Nephrology in Pediatrics at Albert Einstein College of Medicine
Galina Nesterova, M.D.
National Human Genome Research Institute (NHGRI)
Combined Clinical and Molecular Genetics Conference
Topic: Cystinosis, a lysosomal storage disease

Thursday, May 17, 2012

Dean Salisbury, Ph.D.
Director, Cognitive Neuroscience Laboratory, McLean Hospital
Associate Professor, Department of Psychiatry, Harvard Medical School
Neurophysiology of sensory memory: A potential tool for early diagnosis of schizophrenia

Wednesday, May 9, 2012

John Foxe, Ph.D.
Professor of Pediatrics and Neuroscience, and Director of CERC at Albert Einstein College of Medicine (AECOM)
Sophie Molholm, Ph.D.
Associate Professor of Pediatrics and Neuroscience, and Muriel and Harold Block Faculty Scholar in Mental Illness at AECOM
Multisensory Processing in Children with Autism and Sensory Processing Disorder

Tuesday, April 24, 2012

Clayton Curtis, Ph.D.
Associate Professor of Psychology, Department of Psychology and Center for Neural Science, New York University
Topographical Maps of Prioritized Space in Frontal and Parietal Cortex

Tuesday, April 10, 2012

Edmund Lalor, Ph.D.
Assistant Professor, School of Engineering & Institute of Neuroscience, Trinity College Dublin, Ireland
Towards Improved Specificity and Flexibility in EEG-based Sensory Research: Cognitive and Clinical Applications

Friday, April 6, 2012

John Jeka, Ph.D.
Professor, Department of Kinesiology, University of Maryland
Multisensory Fusion and Human Balance Control

Tuesday, March 27, 2012

Brian Keane, Ph.D.
Research Associate at UMDNJ - Robert Wood Johnson Medical School and Rutgers University Center for Cognitive Science
Perceptual Organization Deficits in Schizophrenia: Why Do They Happen and Why Should We Care?

Monday, March 5, 2012

Catherine Lord, Ph.D.
Director of the Center for Autism and the Developing Brain (CADB), a subsidiary of Weill Cornell Medical College and New York Presbyterian Hospital
Longitudinal Studies in the Autism Spectrum Disorders: From 2 to 22

Wednesday, February 29, 2012

Rare People and Rare Talents on a Rare Day
A Special Concert in Celebration of Rare Disease Day