Publications

Hope Center Member Publications

Scopus list of publications for January 30, 2023

Polyphasic circadian neural circuits drive differential activities in multiple downstream rhythmic centers” (2023) Current Biology

Polyphasic circadian neural circuits drive differential activities in multiple downstream rhythmic centers
(2023) Current Biology, 33 (2), pp. 351-363.e3. 

Liang, X., Holy, T.E., Taghert, P.H.

Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Circadian clocks align various behaviors such as locomotor activity, sleep/wake, feeding, and mating to times of day that are most adaptive. How rhythmic information in pacemaker circuits is translated to neuronal outputs is not well understood. Here, we used brain-wide, 24-h in vivo calcium imaging in the Drosophila brain and searched for circadian rhythmic activity among identified clusters of dopaminergic (DA) and peptidergic neurosecretory (NS) neurons. Such rhythms were widespread and imposed by the PERIOD-dependent clock activity within the ∼150-cell circadian pacemaker network. The rhythms displayed either a morning (M), evening (E), or mid-day (MD) phase. Different subgroups of circadian pacemakers imposed neural activity rhythms onto different downstream non-clock neurons. Outputs from the canonical M and E pacemakers converged to regulate DA-PPM3 and DA-PAL neurons. E pacemakers regulate the evening-active DA-PPL1 neurons. In addition to these canonical M and E oscillators, we present evidence for a third dedicated phase occurring at mid-day: the l-LNv pacemakers present the MD activity peak, and they regulate the MD-active DA-PPM1/2 neurons and three distinct NS cell types. Thus, the Drosophila circadian pacemaker network is a polyphasic rhythm generator. It presents dedicated M, E, and MD phases that are functionally transduced as neuronal outputs to organize diverse daily activity patterns in downstream circuits. © 2022 Elsevier Inc.

Author Keywords
calcium;  circadian physiology;  dopamine;  Drosophila;  GCaMP6;  neuronal pacemakers;  peptidergic

Funding details
National Institutes of HealthNIHR01 DP1 DA035081, R01 GM127508, R01 NS068409, R01 NS099332, R24 NS086741
Center for Cellular Imaging, Washington UniversityWUCCI
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis

Document Type: Article
Publication Stage: Final
Source: Scopus

TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4” (2023) Neuron

TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4
(2023) Neuron, 111 (2), pp. 202-219.e7. Cited 1 time.

Gratuze, M.a , Schlachetzki, J.C.M.b , D’Oliveira Albanus, R.c , Jain, N.a , Novotny, B.c , Brase, L.c , Rodriguez, L.a , Mansel, C.a , Kipnis, M.a , O’Brien, S.b , Pasillas, M.P.b , Lee, C.a , Manis, M.a , Colonna, M.d , Harari, O.c , Glass, C.K.b , Ulrich, J.D.a , Holtzman, D.M.a

a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, United States
c Department of Psychiatry, NeuroGenomics and Informatics Center, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, United States
d Department of Pathology and Immunology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer’s disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4. © 2022 Elsevier Inc.

Author Keywords
Alzheimer’s disease;  ApoE4;  microgliosis;  tau pathology;  tau-mediated neurodegeneration;  TREM2

Funding details
4642, CDI-CORE-2015-505, CDI-CORE-2019-813, OD021629
National Institutes of HealthNIH1RF1 AG061060, R01 AG056511, RF1AG047644, RF1NS090934
National Institute on AgingNIAP01AG003991, P01AG026276, P30AG066444, P30AG10161, R01AG044546, R01AG057777, R01AG15819, R01AG17917, R01AG30146, R56AG067764, RF1AG053303, RF1AG57473, U01AD072464, U01AG072464, U01AG32984, U01AG61356
BrightFocus FoundationBFFA2020257F, S10 OD026929
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
University of WashingtonUW
Alzheimer’s Disease Research Center, University of PittsburghADRC

Document Type: Article
Publication Stage: Final
Source: Scopus

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity” (2023) Proceedings of the National Academy of Sciences of the United States of America

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (3), pp. e2207291120. 

Shinoda, K.a b , Li, R.a b , Rezk, A.a b , Mexhitaj, I.a b , Patterson, K.R.a b , Kakara, M.a b , Zuroff, L.a b , Bennett, J.L.c , von Büdingen, H.-C.d , Carruthers, R.e , Edwards, K.R.f , Fallis, R.g , Giacomini, P.S.h , Greenberg, B.M.i , Hafler, D.A.j , Ionete, C.k , Kaunzner, U.W.l , Lock, C.B.m , Longbrake, E.E.n , Pardo, G.o , Piehl, F.p q r , Weber, M.S.s t u , Ziemssen, T.v , Jacobs, D.a b , Gelfand, J.M.w x , Cross, A.H.y , Cameron, B.z , Musch, B.z , Winger, R.C.z , Jia, X.z , Harp, C.T.z , Herman, A.z , Bar-Or, A.a b aa

a Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
b Center for Neuroinflammation and Experimental Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
c Departments of Neurology and Ophthalmology, Programs in Neuroscience and Immunology, University of Colorado School of Medicine, Aurora, CO 80045, United States
d F. Hoffmann-La Roche, Basel, 4070, Switzerland
e Department of Medicine, University of British Columbia, Vancouver, Canada
f Multiple Sclerosis Center of Northeastern New York, Comprehensive MS Care Center Affiliated with the National MS Society, Latham, NY 12110
g Department of Neurology, Ohio State University Medical Center, Columbus, OH 43210, United States
h Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
i Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
j Departments of Neurology and Immunobiology, Yale School of Medicine, CT 06510, New Haven, United States
k Department of Neurology, University of Massachusetts Medical School, Worcester, United Kingdom
l Judith Jaffe Multiple Sclerosis Center, Weill Cornell Medicine, NY, NY 10021, United States
m Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304
n Department of Neurology, Yale University, CT 06510, New Haven, United States
o Oklahoma Medical Research Foundation, Multiple Sclerosis Center of Excellence, Oklahoma City, OK 73104, United States
p Department of Clinical Neuroscience, Karolinska InstituteStockholm SE-171 76, Sweden
q Department of Neurology, Karolinska University HospitalStockholm SE-171 77, Sweden
r Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, Karolinska InstituteStockholm SE-171 77, Sweden
s Institute of Neuropathology, University Medical Center, 37075 Göttingen, Germany
t Department of Neurology, University Medical Center, 37075 Göttingen, Germany
u Fraunhofer-Institute for Translational Medicine and Pharmackology ITMP, 37075 Göttingen, Germany
v Department of Neurology, Center of Clinical Neuroscience, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, 01307, Germany
w Weill Institute for Neurosciences, University of California, San Francisco, CA 94158
x Department of Neurology, University of California, San Francisco, CA 94158
y Department of Neurology, Washington University School of MedicineSaint Louis MO 63110, Seychelles
z Genentech, Inc., South San Francisco, CA 94080
aa Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, United States

Abstract
A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Author Keywords
anti-CD20 therapy;  CD20-expressing T cells;  CD20dim T cells;  CD20dimCD8+ T cells;  ocrelizumab

Document Type: Article
Publication Stage: Final
Source: Scopus

Thin-film optical-acoustic combiner enables high-speed wide-field multi-parametric photoacoustic microscopy in reflection mode” (2023) Optics Letters

Thin-film optical-acoustic combiner enables high-speed wide-field multi-parametric photoacoustic microscopy in reflection mode
(2023) Optics Letters, 48 (2), pp. 195-198. 

Zhong, F., Hu, S.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Multi-parametric photoacoustic microscopy (PAM) is uniquely capable of simultaneous high-resolution mapping of blood oxygenation and flow in vivo. However, its speed has been limited by the dense sampling required for blood flow quantification. To overcome this limitation, we have developed a high-speed multi-parametric PAM system, which enables simultaneous acquisition of ∼500 densely sampled B-scans by superposing the rapid optical scanning across the line-shaped focus of a cylindrically focused ultrasonic transducer over the conventional mechanical scan of the optical-acoustic dual foci. A novel, to the best of our knowledge, optical-acoustic combiner (OAC) is designed and implemented to accommodate the short working distance of the transducer, enabling convenient confocal alignment of the dual foci in reflection mode. A resonant galvanometer (GM) provides stabilized high-speed large-angle scanning. This new system can continuously monitor microvascular blood oxygenation (sO2) and flow over a 4.5×3 mm2 area in the awake mouse brain with high spatial and temporal resolutions (6.9 μm and 0.3 Hz, respectively). c 2023 Optica Publishing Group. © 2023 Authors. All rights reserved.

Funding details
National Science FoundationNSF2023988
National Institute of Mental HealthNIMH099261, 120481

Document Type: Article
Publication Stage: Final
Source: Scopus

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease” (2023) eNeuro

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease
(2023) eNeuro, 10 (1), art. no. ENEURO.0483-22.2022, . 

Iannitelli, A.F.a , Kelberman, M.A.a , Lustberg, D.J.a , Korukonda, A.a , McCann, K.E.a , Mulvey, B.b , Segal, A.a , Liles, L.C.a , Sloan, S.A.a , Dougherty, J.D.b c , Weinshenker, D.a

a Department of Human Genetics, Emory University, School of Medicine, Atlanta, GA 30322, United States
b Department of Genetics, Washington University, School of Medicine, St. Louis, MO 63110, United States
c Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha- synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin DSP-4, which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (2 doses of 50 mg/kg, 1 week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms. © 2022 Iannitelli et al.

Author Keywords
Alzheimer’s disease;  DSP-4;  locus coeruleus;  mice;  norepinephrine;  Parkinson’s disease

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAAG061175, AG079199
National Institute of Neurological Disorders and StrokeNINDSNS129168
National Institute of Environmental Health SciencesNIEHSES12870
School of Medicine, Emory UniversityUL1TR002378

Document Type: Article
Publication Stage: Final
Source: Scopus

Cross-sectional and longitudinal comparisons of biomarkers and cognition among asymptomatic middle-aged individuals with a parental history of either autosomal dominant or late-onset Alzheimer’s disease” (2023) Alzheimer’s and Dementia

Cross-sectional and longitudinal comparisons of biomarkers and cognition among asymptomatic middle-aged individuals with a parental history of either autosomal dominant or late-onset Alzheimer’s disease
(2023) Alzheimer’s and Dementia, . 

Xiong, C.a b c d , McCue, L.M.d , Buckles, V.a b c , Grant, E.d , Agboola, F.d , Coble, D.d , Bateman, R.J.a b c , Fagan, A.M.a b c , Benzinger, T.L.S.a b e f , Hassenstab, J.a b c g , Schindler, S.E.a b c , McDade, E.a b c , Moulder, K.a b c , Gordon, B.A.a b e g , Cruchaga, C.a h , Day, G.S.i , Ikeuchi, T.j , Suzuki, K.k , Allegri, R.F.l , Vöglein, J.m n , Levin, J.m n o , Morris, J.C.a b c p q r , and Dominantly Inherited Alzheimer Network (DIAN)s

a Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
b The Dominantly Inherited Alzheimer Network, Washington University, St. Louis, MO, United States
c Department of Neurology, Washington University, St. Louis, MO, United States
d Division of Biostatistics, Washington University, St. Louis, MO, United States
e Department of Radiology, Washington University, St. Louis, MO, United States
f Department of Neurological Surgery, Washington University, St. Louis, MO, United States
g Department of Psychology, Washington University, St. Louis, MO, United States
h Department of Psychiatry, Washington University, St. Louis, MO, United States
i Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, United States
j Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
k The University of Tokyo, Tokyo, Japan
l Institute for Neurological Research Fleni, Buenos Aires, Argentina
m Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
n German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
o Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
p Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
q Department of Physical Therapy, Washington University, St. Louis, MO, United States
r Department of Occupational Therapy, Washington University, St. Louis, MO, United States

Abstract
Background: Comparisons of late-onset Alzheimer’s disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. Methods: We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound-B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non-carriers (NON-MCs), and ACS participants with a positive (FH+) and negative (FH–) family history of LOAD. Results: At baseline, MCs had the lowest age-adjusted level of CSF Aβ42 and the highest levels of total and phosphorylated tau-181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline. Discussion: Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist. © 2023 the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease (AD);  autosomal dominant Alzheimer’s disease (ADAD), cerebrospinal fluid (CSF);  magnetic resonance imaging (MRI);  Pittsburgh compound-B (PiB);  positron emission tomography (PET)

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01 AG053550, UF1AG032438
Biogen
Japan Agency for Medical Research and DevelopmentAMEDJP21dk0207049, K23AG064029
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development” (2023) Nature Genetics

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
(2023) Nature Genetics, . 

Chung, C.a b , Yang, X.a b , Bae, T.c , Vong, K.I.a b , Mittal, S.a b , Donkels, C.d , Westley Phillips, H.e , Li, Z.a b , Marsh, A.P.L.a b , Breuss, M.W.a b f , Ball, L.L.a b , Garcia, C.A.B.g , George, R.D.a b , Gu, J.a b , Xu, M.a b , Barrows, C.a b , James, K.N.a b , Stanley, V.a b , Nidhiry, A.S.a b , Khoury, S.a b , Howe, G.a b , Riley, E.a b , Xu, X.a b , Copeland, B.a b , Wang, Y.c , Kim, S.H.h , Kang, H.-C.i , Schulze-Bonhage, A.j , Haas, C.A.d j , Urbach, H.k , Prinz, M.j l m , Limbrick, D.D., Jr.n , Gurnett, C.A.n , Smyth, M.D.o , Sattar, S.p , Nespeca, M.p , Gonda, D.D.p , Imai, K.q , Takahashi, Y.q , Chen, H.-H.r , Tsai, J.-W.s , Conti, V.t , Guerrini, R.t , Devinsky, O.u , Silva, W.A., Jr.v , Machado, H.R.g , Mathern, G.W.e , Abyzov, A.c , Baldassari, S.w , Baulac, S.w , Gleeson, J.G.x , Jones, M.x , Masser-Frye, D.x , Sattar, S.x , Nespeca, M.x , Gonda, D.D.x , Imai, K.y , Takahashi, Y.y , Chen, H.-H.z , Tsai, J.-W.aa , Conti, V.ab , Guerrini, R.ac , Devinsky, O.ad , Machado, H.R.ae , Garcia, C.A.B.ae , Silva, W.A., Jr.ae , Kim, S.H.af , Kang, H.-C.af , Alanay, Y.ag , Kapoor, S.ah , Haas, C.A.ai , Ramantani, G.aj , Feuerstein, T.aj , Blumcke, I.ak , Busch, R.ak , Ying, Z.ak , Biloshytsky, V.al , Kostiuk, K.al , Pedachenko, E.al , Mathern, G.W.am , Gurnett, C.A.an , Smyth, M.D.an , Helbig, I.ao , Kennedy, B.C.ao , Liu, J.ap , Chan, F.ap , Krueger, D.aq , Frye, R.ab , Wilfong, A.ab , Adelson, D.ab , Gaillard, W.ar , Oluigbo, C.ar , Anderson, A.as , Lee, A.at , Huang, A.Y.at , D’Gama, A.at , Dias, C.at , Walsh, C.A.at , Maury, E.at , Ganz, J.at , Lodato, M.at , Miller, M.at , Li, P.at , Rodin, R.at , Borges-Monroy, R.at , Hill, R.at , Bizzotto, S.at , Khoshkhoo, S.at , Kim, S.at , Zhou, Z.at , Lee, A.au , Barton, A.au , Galor, A.au , Chu, C.au , Bohrson, C.au , Gulhan, D.au , Maury, E.au , Lim, E.au , Lim, E.au , Melloni, G.au , Cortes, I.au , Lee, J.au , Luquette, J.au , Yang, L.au , Sherman, M.au , Coulter, M.au , Kwon, M.au , Park, P.J.au , Borges-Monroy, R.au , Lee, S.au , Kim, S.au , Lee, S.au , Viswanadham, V.au , Dou, Y.au , Chess, A.J.av , Jones, A.av , Rosenbluh, C.av , Akbarian, S.av , Langmead, B.aw , Thorpe, J.aw , Cho, S.aw , Jaffe, A.ax , Paquola, A.ax , Weinberger, D.ax , Erwin, J.ax , Shin, J.ax , McConnell, M.ax , Straub, R.ax , Narurkar, R.ax , Abyzov, A.ay , Bae, T.ay , Jang, Y.ay , Wang, Y.ay , Addington, A.az , Senthil, G.az , Molitor, C.ba , Peters, M.ba , Gage, F.H.bb , Wang, M.bb , Reed, P.bb , Linker, S.bb , Urban, A.bc , Zhou, B.bc , Pattni, R.bc , Zhu, X.bc , Amero, A.S.bd , Juan, D.bd , Povolotskaya, I.bd , Lobon, I.bd , Moruno, M.S.bd , Perez, R.G.bd , Marques-Bonet, T.bd , Soriano, E.be , Mathern, G.bf , Antaki, D.bg , Averbuj, D.bg , Courchesne, E.bg , Gleeson, J.G.bg , Ball, L.L.bg , Breuss, M.W.bg , Roy, S.bg , Yang, X.bg , Chung, C.bg , Sun, C.bh , Flasch, D.A.bh , Trenton, T.J.F.bh , Kopera, H.C.bh , Kidd, J.M.bh , Moldovan, J.B.bh , Moran, J.V.bh , Kwan, K.Y.bh , Mills, R.E.bh , Emery, S.B.bh , Zhou, W.bh , Zhao, X.bh , Ratan, A.bi , Cherskov, A.bj , Jourdon, A.bj , Vaccarino, F.M.bj , Fasching, L.bj , Sestan, N.bj , Pochareddy, S.bj , Scuder, S.bj , Gleeson, J.G.a b , Focal Cortical Dysplasia Neurogenetics Consortiumbk , Brain Somatic Mosaicism Networkbk

a Department of Neurosciences, University of California San Diego, La JollaCA, United States
b Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States
c Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
d Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
e Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, United States
f Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Aurora, Aurora, CO, United States
g Laboratory of Pediatric Neurosurgery and Developmental Neuropathology, Department of Surgery and Anatomy, University of São Paulo, Ribeirão Preto, Brazil
h Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
i Division of Pediatric Neurology, Department of Pediatrics, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, South Korea
j Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
k Department of Neuroradiology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
l Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany
m Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
n Department of Neurology, St. Louis Children’s Hospital, Washington University St Louis, Washington, MO, United States
o Department of Neurosurgery, St. Louis Children’s Hospital, Washington University St Louis, Washington, MO, United States
p Epilepsy Center, Rady Children’s Hospital, San Diego, CA, United States
q National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
r Division of Pediatric Neurosurgery, The Neurological Institute, Taipei Veterans General Hospital, Taipei City, Taiwan
s Institute of Brain Science, Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
t Pediatric Neurology Unit and Laboratories, IRCCS Meyer Children’s Hospital University of Florence, Firenze, Italy
u Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Health, New York, NY, United States
v Department of Genetics, Center for Cell-Based Therapy, Center for Integrative Systems Biology, University of São Paulo, Ribeirão Preto, Brazil
w Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France
x Rady Children’s Hospital, San Diego, CA, United States
y NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan
z Taipei Veterans General Hospital, Taipei City, Taiwan
aa National Yang Ming Chiao Tung University, Taipei City, Taiwan
ab Barrow Neurological Institute at Phoenix Children’s Hospital, University Arizona College of Medicine, Phoenix, AZ, United States
ac IRCCS Meyer Children’s Hospital, University of Florence, Firenze, Italy
ad New York University Langone Health, New York, NY, United States
ae University of São Paulo, Ribeirão Preto, Brazil
af Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
ag Acibadem Hospital, Istanbul, Turkey
ah Lok Nayak Hospital & Maualana Azad Medical Center, New Delhi, India
ai University of Freiburg, Freiburg, Germany
aj Albert-Ludwigs University, Freiburg, Germany
ak University Hopsital Erlangen, Erlangen, Germany
al Romodanov Institute of Neurosurgery, Kyiv, Ukraine
am University of California at Los Angeles, Los Angeles, CA, United States
an St. Louis Children’s Hospital, Washington University St Louis, Washington, MO, United States
ao Children’s Hospital Philadelphia, Philadelphia, PA, United States
ap Brown University, Providence, RI, United States
aq Cincinnati Children’s Hospital, Cincinnati, OH, United States
ar Children’s National Hospital, Washington, DC, United States
as Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, United States
at Boston Children’s Hospital, Boston, MA, United States
au Harvard University, Boston, MA, United States
av Icahn School of Medicine at Mount Sinai, New York, NY, United States
aw Kennedy Krieger Institute, Baltimore, MD, United States
ax Lieber Institute for Brain Development, Baltimore, MD, United States
ay Mayo Clinic, Rochester, MN, United States
az National Institute of Mental Health (NIMH), Bethesda, MD, United States
ba Sage Bionetworks Seattle, Seattle, WA, United States
bb Salk Institute for Biological Studies, La Jolla, CA, United States
bc Stanford University, CA, United States
bd Universitat Pompeu Fabra, Barcelona, Spain
be University of Barcelona, Barcelona, Spain
bf University of California, Los Angeles, CA, United States
bg University of California, San Diego, La Jolla, CA, United States
bh University of Michigan, Ann Arbor, MI, United States
bi University of Virginia, Charlottesville, VA, United States
bj Yale University, New Haven, CT, United States

Abstract
Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIHS10OD026929
National Institute of Mental HealthNIMHR01MH124890, U01MH108898
National Institute on AgingNIAR21AG070462
National Cancer InstituteNCIP30CA23100
National Institute of Neurological Disorders and StrokeNINDSR01NS083823
Brain and Behavior Research FoundationBBRF30598
University of California, San DiegoUCSD
National Alliance for Research on Schizophrenia and DepressionNARSAD
Ente Cassa di Risparmio di Firenze
Regione Toscana

Document Type: Article
Publication Stage: Article in Press
Source: Scopus