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Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria.
- Source :
-
Acta neuropathologica communications [Acta Neuropathol Commun] 2020 Mar 20; Vol. 8 (1), pp. 38. Date of Electronic Publication: 2020 Mar 20. - Publication Year :
- 2020
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Abstract
- Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500Gā>āA (p.R167Q) mutation with ~ā5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.
- Subjects :
- Anhedonia
Animals
Cell Proliferation
Depression genetics
Depression physiopathology
Depression psychology
Disease Models, Animal
Elevated Plus Maze Test
Gene Knock-In Techniques
Hindlimb Suspension
Hippocampus physiopathology
Homozygote
Immunohistochemistry
Long-Term Potentiation
Mice
Microscopy, Fluorescence
Myelin Sheath metabolism
Neural Inhibition
Neural Stem Cells
Neurogenesis
Neuronal Plasticity
Patch-Clamp Techniques
Porphyria, Acute Intermittent genetics
Porphyria, Acute Intermittent physiopathology
Porphyria, Acute Intermittent psychology
Behavior, Animal
Depression metabolism
Hippocampus metabolism
Hydroxymethylbilane Synthase genetics
Mitochondria metabolism
Porphyria, Acute Intermittent metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2051-5960
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Acta neuropathologica communications
- Publication Type :
- Academic Journal
- Accession number :
- 32197664
- Full Text :
- https://doi.org/10.1186/s40478-020-00910-z