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Functional Characterization of Na+/H+ Exchangers of Intracellular Compartments Using Proton-killing Selection to Express Them at the Plasma Membrane
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SLC13A5/sodium-citrate co-transporter overexpression causes disrupted white matter integrity and an autistic-like

Michael J Rigby1,2,3, Nicola Salvatore Orefice1,2, Alexis J Lawton4

  • 1Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.

Brain Communications
|February 11, 2022
PubMed

Insights

Altered cellular metabolism, specifically citrate to acetyl-CoA flux, is linked to autism. Neuron-specific overexpression of SLC13A5 in mice caused autistic-like behaviors and disrupted brain structure.

Area of Science:

  • Neuroscience
  • Cellular Metabolism
  • Molecular Biology

Background:

  • Endoplasmic reticulum (ER) Nε-lysine acetylation is crucial for protein quality control in the secretory pathway.
  • Dysfunctional ER acetylation, exemplified by AT-1 transporter overexpression, leads to altered glycoprotein flux and autistic-like phenotypes in mice.
  • Key metabolic players include SLC25A1 (mitochondrial citrate/malate antiporter), SLC13A5 (plasma membrane sodium/citrate symporter), and ATP citrate lyase.

Purpose of the Study:

  • To investigate the impact of neuron-specific SLC13A5 overexpression on mouse behavior and neurobiology.
  • To explore the mechanistic link between intracellular citrate/acetyl-CoA flux and autistic-like phenotypes.

Main Methods:

  • Generation of transgenic mice with neuron-specific overexpression of SLC13A5.
  • Behavioral analysis of mice, including assessment of stereotypies.
  • Histological examination of brain tissue, focusing on white matter integrity and synaptic structures.
  • Proteomic and acetyl-proteomic analysis of hippocampal and cortical tissues.

Main Results:

  • Mice overexpressing neuron-specific SLC13A5 exhibited autistic-like behaviors, notably jumping stereotypy.
  • Disrupted white matter integrity and altered synaptic structure and function were observed.
  • Proteomic and acetyl-proteomic analyses revealed unique adaptive responses in the hippocampus and cortex.

Conclusions:

  • Neuron-specific SLC13A5 overexpression induces autistic-like behaviors and associated neuropathological changes.
  • Aberrant intracellular citrate/acetyl-CoA flux represents a potential mechanism underlying the development of autistic-like phenotypes.
  • Metabolic adaptations in the brain play a significant role in the observed SLC13A5 transgenic phenotype.

Keywords:
AT-1SLC13A5acetyl-CoAcitratelysine acetylation

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