Apreclinical investigation of the neuropsychiatric manifestations of acute intermittent porphyria using a mouse model system
Acute intermittent porphyria (AIP) is a rare hereditary metabolic disorder with a genetically determined dysfunction of the heme biosynthetic pathway caused by a porphobilinogen deaminase (=hydroxymethylbilane synthase) deficiency. The consequence of the enzymatic dysfunction is an accumulation of the toxic metabolic intermediates of heme, particularly aminolevulinic acid (ALA) and porphobilinogen (PBG) which is thought to underlie the varying presentation of symptoms, include abdominal pain, peripheral neuropathy and psychiatric manifestations, associated with acute attacks (Puy H 2010). While neuropsychiatric conditions, including depression and anxiety are reported in up to 50% of the AIP population, it is still unclear whether they present a symptom or a trigger of the disorder and the underlying neuropathological are poorly understood (Crimlisk HL 1997, Laiwah AC, 1985).
Here we intend to investigate the relationship between emotional disturbances and AIP in a genetic mouse model of AIP (generated by the laboratory of Prof. Robert Desnick, Mt. Sinai, New York) in which a point mutation in the PBGD gene (R167Q) leads to a 95% reduction of enzyme activity in mutants (KO) as compared to wild-type (WT) controls. We aim to behaviorally characterize this mouse strain, focusing on anxiety-like and depression-like behaviors, complemented by the evaluation of general behavioral functions, including exploratory and locomotor activity. We further seek to investigate the molecular underpinnings underlying the potential behavioral phenotype, focusing in the analysis of the γ-Aminobutyric acid (GABA)-ergic system, based upon evidence for an antagonistic and damaging effect of ALA on GABAA receptors (Demasi et al. 1996, Pierach and Edwards, 1978), and the documented relevance of GABA-mediated signaling in the pathogenesis of anxiety and depressive disorders (see for review Smith et al. 2012).
First preliminary data indicate enhanced depression-like behavior in KO as compared to wild-type littermate controls as well as impaired motor coordination. While motor dysfunctions have been previously described in another mouse model of AIP (Lindberg RL 1996 and 1999, Unzu C 2010) and thought to reflect peripheral neuropathy, a hallmark of acute attacks in AIP patients (Lindberg RL 1996), this is the first experimental evidence for emotional disturbances in a preclinical model of AIP.
Additionally, we have obtained indications that the observed augmented depression-like behavior, can be reversed by conventional antidepressant treatment using a selective serotonin reuptake inhibitor, a finding of potential translational relevance for the clinical practice.
Further planned investigations involve the neuropathohistological characterization of brains of KO and WT mice by immunohistochemistry in order to reveal potential morphological correlates of the observed behavioral alterations. In parallel, adult hippocampal neurogenesis, will be evaluated in the hippocampal dentate gyrus of KO and WT mice as alterations in hippocampal neurogenesis - potentially resulting from permanent (developmental) deficiency in GABAA receptors - may relate to the increase in depression-like behavior in KO mice.
Molecular analysis will focus on an in-depth characterization of the GABAA receptor and subtype system in KO as compared to WT mice and an examination of the molecular signal transduction pathway involved.
This first experimental assessment of the role of emotional disturbances in the pathogenesis of AIP and the elucidation of its molecular underpinnings may aid in the identification of therapeutically amenable targets for preventive and symptomatic treatment of patients suffering from AIP.