Knockdown of Myo-Inositol Transporter SMIT1 Normalizes Cholinergic and Glutamatergic Function in an Immortalized Cell Line Established from the Cerebral Cortex of a Trisomy 16 Fetal Mouse, an Animal Model of Human Trisomy 21 (Down Syndrome)

Ana María Cárdenas, Paola Fernández-Olivares, Ignacio Díaz-Franulic, Arlek M. González-Jamett, Takeshi Shimahara, Juan Segura-Aguilar, Raúl Caviedes, Pablo Caviedes

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

The Na+/myo-inositol cotransporter (SMIT1) is overexpressed in human Down syndrome (DS) and in trisomy 16 fetal mice (Ts16), an animal model of the human condition. SMIT1 overexpression determines increased levels of intracellular myo-inositol, a precursor of phophoinositide synthesis. SMIT1 is overexpressed in CTb cells, an immortalized cell line established from the cerebral cortex of a Ts16 mouse fetus. CTb cells exhibit impaired cytosolic Ca2+ signals in response to glutamatergic and cholinergic stimuli (increased amplitude and delayed time-dependent kinetics in the decay post-stimulation), compared to our CNh cell line, derived from the cerebral cortex of a euploid animal. Considering the role of myo-inositol in intracellular signaling, we normalized SMIT1 expression in CTb cells using specific mRNA antisenses. Forty-eight hours post-transfection, SMIT1 levels in CTb cells reached values comparable to those of CNh cells. At this time, decay kinetics of Ca2+ signals induced by either glutamate, nicotine, or muscarine were accelerated in transfected CTb cells, to values similar to those of CNh cells. The amplitude of glutamate-induced cytosolic Ca2+ signals in CTb cells was also normalized. The results suggest that SMIT1 overexpression contributes to abnormal cholinergic and glutamatergic Ca2+ signals in the trisomic condition, and knockdown of DS-related genes in our Ts16-derived cell line could constitute a relevant tool to study DS-related neuronal dysfunction.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalNeurotoxicity Research
Volume32
Issue number4
DOIs
Publication statusAccepted/In press - 10 Jul 2017

Keywords

  • Calcium
  • Cholinergic
  • Down syndrome
  • Glutamate
  • Myo-inositol
  • SMIT1

ASJC Scopus subject areas

  • General Neuroscience
  • Toxicology

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