GABA A receptor subunit deregulation in the hippocampus of human foetuses with Down syndrome

Brain Struct Funct. 2018 Apr;223(3):1501-1518. doi: 10.1007/s00429-017-1563-3. Epub 2017 Nov 22.

Abstract

The function, regulation and cellular distribution of GABAA receptor subunits have been extensively documented in the adult rodent brain and are linked to numerous neurological disorders. However, there is a surprising lack of knowledge on the cellular (sub-) distribution of GABAA receptor subunits and of their expressional regulation in developing healthy and diseased foetal human brains. To propose a role for GABAA receptor subunits in neurodevelopmental disorders, we studied the developing hippocampus of normal and Down syndrome foetuses. Among the α1-3 and γ2 subunits probed, we find significantly altered expression profiles of the α1, α3 and γ2 subunits in developing Down syndrome hippocampi, with the α3 subunit being most affected. α3 subunits were selectively down-regulated in all hippocampal subfields and developmental periods tested in Down syndrome foetuses, presenting a developmental mismatch by their adult-like distribution in early foetal development. We hypothesized that increased levels of the amyloid precursor protein (APP), and particularly its neurotoxic β-amyloid (1-42) fragment, could disrupt α3 gene expression, likely by facilitating premature neuronal differentiation. Indeed, we find increased APP content in the hippocampi of the Down foetuses. In a corresponding cellular model, soluble β-amyloid (1-42) administered to cultured SH-SY5Y neuroblastoma cells, augmented by retinoic acid-induced differentiation towards a neuronal phenotype, displayed a reduction in α3 subunit levels. In sum, this study charts a comprehensive regional and subcellular map of key GABAA receptor subunits in identified neuronal populations in the hippocampus of healthy and Down syndrome foetuses and associates increased β-amyloid load with discordant down-regulation of α3 subunits.

Keywords: Cell migration; Differentiation; Interneuron; Neurodegeneration; Pyramidal cell.

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Animals, Newborn
  • Case-Control Studies
  • Doublecortin Domain Proteins
  • Down Syndrome / genetics
  • Down Syndrome / pathology*
  • Embryo, Mammalian
  • Female
  • Fetus
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / physiology*
  • Gestational Age
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Hippocampus / growth & development
  • Hippocampus / metabolism*
  • Hippocampus / pathology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuroblastoma / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuropeptides / metabolism
  • POU Domain Factors / genetics
  • POU Domain Factors / metabolism
  • Peptide Fragments / pharmacology
  • Protein Subunits / genetics
  • Protein Subunits / metabolism*
  • Receptors, GABA-A / metabolism*
  • Tretinoin / pharmacology
  • Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
  • Young Adult

Substances

  • Amyloid beta-Peptides
  • Doublecortin Domain Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • POU Domain Factors
  • Peptide Fragments
  • Protein Subunits
  • Receptors, GABA-A
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • Viaat protein, mouse
  • amyloid beta-protein (1-42)
  • Pou3f3 protein, mouse
  • Tretinoin
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1