Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia.
22q11.2 deletion carriers show specific cognitive deficits, and ∼30% of them develop schizophrenia. One of the disrupted genes is ZDHHC8, which encodes for a palmitoyltransferase. We show that Zdhhc8-deficient mice have reduced palmitoylation of proteins that regulate axonal growth and branching. Analysis of axonal projections of pyramidal neurons from both Zdhhc8-deficient and Df(16)A(+/-) mice, which model the 22q11.2 deletion, revealed deficits in axonal growth and terminal arborization, which can be prevented by reintroduction of active ZDHHC8 protein. Impaired terminal arborization is accompanied by a reduction in the strength of synaptic connections and altered functional connectivity and working memory. The effect of ZDHHC8 is mediated in part via Cdc42-dependent modulation of Akt/Gsk3β signaling at the tip of the axon and can be reversed by pharmacologically decreasing Gsk3β activity during postnatal brain development. Our findings provide valuable mechanistic insights into the cognitive and psychiatric symptoms associated with a schizophrenia-predisposing mutation.
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Jun
J
Mukai
Department of Psychiatry, New York State Psychiatry Institute, New York, NY 10032, USA; Pharmacology Research Laboratories I, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan.
Makoto
M
Tamura
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Karine
K
Fénelon
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Psychiatry, New York State Psychiatry Institute, New York, NY 10032, USA.
Andrew M
AM
Rosen
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Timothy J
TJ
Spellman
Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Rujun
R
Kang
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Amy B
AB
MacDermott
Department of Psychiatry, New York State Psychiatry Institute, New York, NY 10032, USA.
Maria
M
Karayiorgou
Department of Psychiatry, New York State Psychiatry Institute, New York, NY 10032, USA.
Joshua A
JA
Gordon
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: jag90@columbia.edu.
Joseph A
JA
Gogos
D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000473:pathology*; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D000075402:Channelrhodopsins; D004062:DiGeorge Syndrome / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000196:embryology / Q000254:growth & development / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016704:Synapsins / Q000378:metabolism
D000075402:Channelrhodopsins; D008565:Membrane Proteins; D016704:Synapsins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000217:Acyltransferases; C534673:ZDHHC8 protein, mouse; D010751:Phosphopyruvate Hydratase