title: Altered behavioral performance and live imaging of circuit-specific neural deficiencies in a zebrafish model for psychomotor retardation.
abstract: The mechanisms and treatment of psychomotor retardation, which includes motor and cognitive impairment, are indefinite. The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked psychomotor retardation characterized by delayed development, severe intellectual disability, muscle hypotonia, and spastic paraplegia, in combination with disturbed thyroid hormone (TH) parameters. AHDS has been associated with mutations in the monocarboxylate transporter 8 (mct8/slc16a2) gene, which is a TH transporter. In order to determine the pathophysiological mechanisms of AHDS, MCT8 knockout mice were intensively studied. Although these mice faithfully replicated the abnormal serum TH levels, they failed to exhibit the neurological and behavioral symptoms of AHDS patients. Here, we generated an mct8 mutant (mct8-/-) zebrafish using zinc-finger nuclease (ZFN)-mediated targeted gene editing system. The elimination of MCT8 decreased the expression levels of TH receptors; however, it did not affect the expression of other TH-related genes. Similar to human patients, mct8-/- larvae exhibited neurological and behavioral deficiencies. High-throughput behavioral assays demonstrated that mct8-/- larvae exhibited reduced locomotor activity, altered response to external light and dark transitions and an increase in sleep time. These deficiencies in behavioral performance were associated with altered expression of myelin-related genes and neuron-specific deficiencies in circuit formation. Time-lapse imaging of single-axon arbors and synapses in live mct8-/- larvae revealed a reduction in filopodia dynamics and axon branching in sensory neurons and decreased synaptic density in motor neurons. These phenotypes enable assessment of the therapeutic potential of three TH analogs that can enter the cells in the absence of MCT8. The TH analogs restored the myelin and axon outgrowth deficiencies in mct8-/- larvae. These findings suggest a mechanism by which MCT8 regulates neural circuit assembly, ultimately mediating sensory and motor control of behavioral performance. We also propose that the administration of TH analogs early during embryo development can specifically reduce neurological damage in AHDS patients.
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Zada
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Tovin
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Lerer-Goldshtein
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel; Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Gad David
authors.initials: GD
authors.lastname: Vatine
authors.affiliation: The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Appelbaum
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D023061:Gene Order; D018390:Gene Targeting; D007030:Hypothalamo-Hypophyseal System; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D038901:X-Linked Intellectual Disability / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology*; D027501:Monocarboxylic Acid Transporters / Q000235:genetics; D009043:Motor Activity / Q000235:genetics; D009123:Muscle Hypotonia / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology*; D009133:Muscular Atrophy / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology*; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism; D051579:Neurogranin / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D017440:Photoperiod; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics; D013963:Thyroid Hormones / Q000494:pharmacology; D015027:Zebrafish; D016335:Zinc Fingers
chemical_list: D051741:Kruppel-Like Transcription Factors; D027501:Monocarboxylic Acid Transporters; C570017:Slc16a2 protein, zebrafish; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D051579:Neurogranin