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GABA_A receptor subunit deregulation in the hippocampus of human foetuses with Down syndrome.

ABSTRACT: The function, regulation and cellular distribution of GABA_A 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 GABA_A receptor subunits and of their expressional regulation in developing healthy and diseased foetal human brains. To propose a role for GABA_A 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 GABA_A 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.

SUBMITTER: Milenkovic I

PROVIDER: S-EPMC5869939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDeath receptor 6 (DR6) is highly expressed in the human brain: it has been shown to induce axon pruning and neuron death via distinct caspases and to mediate axonal degeneration through binding to N-terminal β amyloid precursor protein (N-APP).MethodsWe investigated the expression of DR6 during prenatal and postnatal development in human hippocampus and temporal cortex by immunocytochemistry and Western blot analysis (118 normal human brain specimens; 9 to 41 gestational weeks; 1 day to 7 months postnatally; 3 to 91 years). To investigate the role of N-APP/DR6/caspase 6 pathway in the development of hippocampal Alzheimer's disease (AD)-associated pathology, we examined DR6 immunoreactivity (IR) in the developing hippocampus from patients with Down syndrome (DS; 48 brain specimens; 14 to 41 gestational weeks; 7 days to 8 months postnatally; 15 to 64 years) and in adults with DS and AD.ResultsDR6 was highly expressed in human adult hippocampus and temporal cortex: we observed consistent similar temporal and spatial expression in both control and DS brain. Western blot analysis of total homogenates of temporal cortex and hippocampus showed developmental regulation of DR6. In the hippocampus, DR6 IR was first apparent in the stratum lacunosum-moleculare at 16 weeks of gestation, followed by stratum oriens, radiatum, pyramidale (CA1 to CA4) and molecular layer of the dentate gyrus between 21 and 23 gestational weeks, reaching a pattern similar to adult hippocampus around birth. Increased DR6 expression in dystrophic neurites was detected focally in a 15-year-old DS patient. Abnormal DR6 expression pattern, with increased expression within dystrophic neurites in and around amyloid plaques was observed in adult DS patients with widespread AD-associated neurodegeneration and was similar to the pattern observed in AD hippocampus. Double-labeling experiments demonstrated the colocalization, in dystrophic neurites, of DR6 with APP. We also observed colocalization with hyper-phosphorylated Tau and with caspase 6 (increased in hippocampus with AD pathology) in plaque-associated dystrophic neurites and within the white matter.ConclusionsThese findings demonstrate a developmental regulation of DR6 in human hippocampus and suggest an abnormal activation of the N-APP/DR6/caspase 6 pathway, which can contribute to initiation or progression of hippocampal AD-associated pathology.

Project description:Rationale: Current first-line treatments for stress-related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "?5-PAM"), a positive allosteric modulator selective for ?5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites, has anti-stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with ?5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic ?5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic ?5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to ?5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with ?5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of ?5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

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GABA_A receptor subunit deregulation in the hippocampus of human foetuses with Down syndrome.

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Dataset Information

GABAA receptor subunit deregulation in the hippocampus of human foetuses with Down syndrome.

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OmicsDI is part of the ELIXIR infrastructure

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GABA_A receptor subunit deregulation in the hippocampus of human foetuses with Down syndrome.