Neurobiological underpinnings of depression in acute intermittent porphyria

Acute intermittent porphyria (AIP), an autosomal dominant inborn error of heme biosynthesis, is due to the half- normal activity of hydroxymethylbilane synthase (HMBS). The disease is characterized by life-threatening acute neurovisceral attacks that are precipitated by various factors (e.g. drugs, hormonal changes, fasting) which result in the accumulation of the neurotoxic metabolic precursors, aminolevulinic acid (ALA) and porphobilinogen (PBG). While neuropsychiatric conditions such as depression and anxiety are reported in up to 50% of AIP patients, the underlying pathogenic mechanisms remain unclear. Here we aim to investigate the emotional disturbances in this disease and to elucidate the underlying neurobiological mechanisms using a severely affected AIP knock-in (KI) mouse model which have constitutively elevated ALA and PBG levels in the plasma and peripheral tissues, including the brain. Initial efforts will be directed towards analyzing depression-like and anxiety-related behavior in the KI mice using a battery of standard behavioral tests and additionally controlling for potential confounding alterations in general behavioral functions. We will also evaluate the rate of proliferation and fate of newborn cells in the hippocampus of KI and wildtype (WT) mice as these characteristics have been strongly linked to depression and response to antidepressant treatment. Further, we will monitor neural function electrophysiologically in the hippocampus of the KI and WT mice and neuropathohistologically evaluate KI and WT brains. In the final step we seek to unravel the molecular mechanism(s) involved in the behavioral and neurogenic deficits in AIP focusing on evaluating Gamma-aminobutyric acid (GABA)A receptor density, subtype expression and signaling; ALA has been shown to specifically interact with elements of the GABAergic neurotransmitter system, which is highly implicated in the pathophysiology of mood disorders. The proposed research has the potential to further our understanding of the neural mechanisms underlying and/or mediating depression in AIP. Moreover, the results obtained may provide novel insights into the pathophysiology of mood disorders and lead to the identification of alternative therapeutic strategies.

Acute intermittent porphyria is a hereditary metabolic disorder characterized by hydroxymethylbilane synthase (HMBS) deficiency causing dysfunctional heme biosynthesis. The consequence is an accumulation of the toxic intermediates aminolevulinic acid and porphobilinogen, which cause peripheral neuropathy, tremor, ataxia, and psychiatric manifestations. However, the underlying neuropathological mechanisms of the affective symptoms are poorly understood. To unravel the impact of severe HMBS deficiency on affective behavior and brain physiology, a transgenic mouse model that is biallelic for the Hmbs c.500G>A (p.R167Q) mutation, with ~5% of normal HMBS activity was examined using a multidisciplinary approach spanning in vivo behavioral, ex vivo electrophysiological, biochemical, and molecular techniques was employed. Comprehensive behavioral analyses revealed enhanced depression-like-behavior with an unaltered anxiety phenotype in HMBS-deficient mice. Hypothesis-free RNA sequencing documented altered expression of myelin-relevant transcripts and an oligodendrocytic impairment was independently verified. Notably, a specific mitochondrial energetic deficit was determined biochemically and confirmed functionally in hippocampal neurons of HMBS-deficient mice. Consequently, progenitor cell proliferation and differentiation of newborn cells into mature neurons were deficient in the hippocampal dentate gyrus of mutant mice and paralleled by aberrant long-term potentiation. Collectively an affective derangement in a homozygous dominant mouse model for acute intermittent porphyria was thoroughly characterized. The aberrant mitochondrial function and related myelination impairment were proposed as the relevant pathomechanism contributing to the neuropsychiatric manifestations in acute intermittent porphyria.