Sequential activity of CA1 hippocampal cells constitutes a temporal memory map for associative learning in mice
(2024) Current Biology, 34 (4), pp. 841-854.e4.
Ma, M.a , Simoes de Souza, F.a b , Futia, G.L.c , Anderson, S.R.d , Riguero, J.d e , Tollin, D.d e , Gentile-Polese, A.a , Platt, J.P.f , Steinke, K.g , Hiratani, N.h , Gibson, E.A.c e , Restrepo, D.a e
a Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
b Center for Mathematics, Computation and Cognition, Federal University of ABC, SP, Sao Bernardo do Campo, 09606-045, Brazil
c Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
d Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
e Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
f Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
g Integrated Physiology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
h Department of Neuroscience, Washington University, St. Louis, MO 63110, United States
Abstract
Sequential neural dynamics encoded by time cells play a crucial role in hippocampal function. However, the role of hippocampal sequential neural dynamics in associative learning is an open question. We used two-photon Ca2+ imaging of dorsal CA1 (dCA1) neurons in the stratum pyramidale (SP) in head-fixed mice performing a go-no go associative learning task to investigate how odor valence is temporally encoded in this area of the brain. We found that SP cells responded differentially to the rewarded or unrewarded odor. The stimuli were decoded accurately from the activity of the neuronal ensemble, and accuracy increased substantially as the animal learned to differentiate the stimuli. Decoding the stimulus from individual SP cells responding differentially revealed that decision-making took place at discrete times after stimulus presentation. Lick prediction decoded from the ensemble activity of cells in dCA1 correlated linearly with lick behavior. Our findings indicate that sequential activity of SP cells in dCA1 constitutes a temporal memory map used for decision-making in associative learning. Video abstract: © 2024 Elsevier Inc.
Author Keywords
associative learning; CA1; decision-making; decoding; go-no go; hippocampus; olfactory; time cells
Funding details
National Science FoundationNSFBCS-1926676
National Institutes of HealthNIHR01 DC000566, UF1 NS116241
Document Type: Article
Publication Stage: Final
Source: Scopus
ALS-related p97 R155H mutation disrupts lysophagy in iPSC-derived motor neurons
(2024) Stem Cell Reports, .
Klickstein, J.A.a , Johnson, M.A.a , Antonoudiou, P.b , Maguire, J.b , Paulo, J.A.c , Gygi, S.P.c , Weihl, C.d , Raman, M.a
a Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, United States
b Department of Neuroscience, Tufts University School of Medicine, Boston, MA, United States
c Department of Cell Biology, Harvard Medical School, Boston, MA, United States
d Department of Neurology, Washington University at St. Louis, St. Louis, MO, United States
Abstract
Mutations in the AAA+ ATPase p97 cause multisystem proteinopathy 1, which includes amyotrophic lateral sclerosis; however, the pathogenic mechanisms that contribute to motor neuron loss remain obscure. Here, we use two induced pluripotent stem cell models differentiated into spinal motor neurons to investigate how p97 mutations perturb the motor neuron proteome. Using quantitative proteomics, we find that motor neurons harboring the p97 R155H mutation have deficits in the selective autophagy of lysosomes (lysophagy). p97 R155H motor neurons are unable to clear damaged lysosomes and have reduced viability. Lysosomes in mutant motor neurons have increased pH compared with wild-type cells. The clearance of damaged lysosomes involves UBXD1-p97 interaction, which is disrupted in mutant motor neurons. Finally, inhibition of the ATPase activity of p97 using the inhibitor CB-5083 rescues lysophagy defects in mutant motor neurons. These results add to the evidence that endo-lysosomal dysfunction is a key aspect of disease pathogenesis in p97-related disorders. © 2024 The Author(s)
Author Keywords
ALS; autophagy; galectin; lysophagy; lysosome; mitochondria; p97; proteomics
Funding details
National Institutes of HealthNIH1070479, GM127557, NS123631
Muscular Dystrophy AssociationMDAAA026256, AG031867, AR073317, GM132129, GM133314, GM67945, MH122379, MH128235, NS102937, NS105628
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt
(2024) American Journal of Human Genetics, 111 (3), pp. 487-508.
Shepherdson, J.L.a , Hutchison, K.b , Don, D.W.c , McGillivray, G.d e , Choi, T.-I.c , Allan, C.A.f , Amor, D.J.e g , Banka, S.h i , Basel, D.G.j , Buch, L.D.k , Carere, D.A.l , Carroll, R.m , Clayton-Smith, J.n , Crawford, A.o , Dunø, M.p , Faivre, L.q r , Gilfillan, C.P.s t , Gold, N.B.u v , Gripp, K.W.w , Hobson, E.x , Holtz, A.M.y , Innes, A.M.z , Isidor, B.aa ab , Jackson, A.h i , Katsonis, P.ac , Amel Riazat Kesh, L.x , Küry, S.aa ab , Lecoquierre, F.ad , Lockhart, P.e g , Maraval, J.q r , Matsumoto, N.ae , McCarrier, J.j , McCarthy, J.t , Miyake, N.ae af , Moey, L.H.ag , Németh, A.H.ah ai , Østergaard, E.p aj , Patel, R.ak , Pope, K.e , Posey, J.E.ac , Schnur, R.E.l , Shaw, M.m , Stolerman, E.k , Taylor, J.P.o , Wadman, E.w , Wakeling, E.al , White, S.M.d e g , Wong, L.C.am , Lupski, J.R.ac an ao ap , Lichtarge, O.ac , Corbett, M.A.m , Gecz, J.m aq , Nicolet, C.M.b , Farnham, P.J.b , Kim, C.-H.c , Shinawi, M.ar , Genomics England Research Consortiumas
a Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
c Department of Biology, Chungnam National University, Daejeon, 34134, South Korea
d Victorian Clinical Genetics Services, Parkville, VIC 3052, Australia
e Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia
f Hudson Institute of Medical Research, Monash University, Department of Endocrinology, Monash Health, Melbourne, Australia
g Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia
h Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
i Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom
j Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
k Greenwood Genetic Center, Greenwood, SC, United States
l GeneDx, Gaithersburg, MD 20877, United States
m Adelaide Medical School and Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
n Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, United Kingdom
o Medical Genomics Research, Illumina Inc, San Diego, CA, United States
p Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
q Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d’Enfants, Dijon, France
r INSERM UMR1231, Equipe GAD, Université de Bourgogne-Franche Comté, Dijon, 21000, France
s Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia
t Department of Endocrinology, Eastern Health, Box Hill Hospital, Melbourne, VIC, Australia
u Harvard Medical School, Boston, MA, United States
v Division of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, MA, United States
w Division of Medical Genetics, Nemours Children’s Hospital, Wilmington, DE, United States
x Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, United Kingdom
y Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
z Departments of Medical Genetics and Pediatrics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
aa Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, 44000, France
ab Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du Thorax, Nantes, 44000, France
ac Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
ad Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, Rouen, 76000, France
ae Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
af Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
ag Department of Genetics, Penang General Hospital, Penang, George Town, Malaysia
ah Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
ai Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
aj Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
ak Medical Genetics, Kaiser Permanente Oakland Medical Center, Oakland, CA, United States
al North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
am Medical Genetics, Kaiser Permanente Downey Medical Center, Downey, CA, United States
an Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
ao Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
ap Texas Children’s Hospital, Houston, TX, United States
aq South Australian Health and Medical Research Institute, Adelaide, SA, Australia
ar Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism. © 2024 American Society of Human Genetics
Author Keywords
behavioral problems; congenital anomalies; de novo mutation; developmental delay; hyperparathyroidism; hypotonia; intellectual disability; transcription factor; X-linked; ZFX; zinc finger
Funding details
Chiesi Farmaceutici
Amicus Therapeutics
Document Type: Article
Publication Stage: Final
Source: Scopus
Comparison of Behavioral Effects of GABAergic Low- and High-Efficacy Neuroactive Steroids in the Zebrafish Larvae Assay
(2023) ACS Chemical Neuroscience, .
Germann, A.L., Xu, Y., Covey, D.F., Evers, A.S., Akk, G.
Department of Anesthesiology, Developmental of Biology, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO 63110, United States
Abstract
Activation of the GABAA receptor is associated with numerous behavioral end points ranging from anxiolysis to deep anesthesia. The specific behavioral effect of a GABAergic compound is considered to correlate with the degree of its functional effect on the receptor. Here, we tested the hypothesis that a low-efficacy allosteric potentiator of the GABAA receptor may act, due to a ceiling effect, as a sedative with reduced and limited action. We synthesized a derivative, named (3α,5β)-20-methyl-pregnane-3,20-diol (KK-235), of the GABAergic neurosteroid 5β-pregnane-3α,20α-diol. Using electrophysiology, we showed that KK-235 is a low-efficacy potentiator of the synaptic-type α1β2γ2L GABAA receptor. In the zebrafish larvae behavioral assay, KK-235 was found to only partially block the inverted photomotor response (PMR) and to weakly reduce swimming behavior, whereas the high-efficacy GABAergic steroid (3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile (ACN) fully blocked PMR and spontaneous swimming. Coapplication of KK-235 reduced the potentiating effect of ACN in an electrophysiological assay and dampened its sedative effect in behavioral experiments. We propose that low-efficacy GABAergic potentiators may be useful as sedatives with limited action. © 2024 American Chemical Society.
Author Keywords
behavior; function; GABAA receptor; neuroactive steroids; potentiation; sedatives
Funding details
P50MH122379
National Institute of General Medical SciencesNIGMSR35GM140947, R35GM149287
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus