Ant1 mutant mice bridge the mitochondrial and serotonergic dysfunctions in bipolar disorder

Abstract

Although mitochondrial and serotonergic dysfunctions have been implicated in the etiology of bipolar disorder (BD), the relationship between these unrelated pathways has not been elucidated. A family of BD and chronic progressive external ophthalmoplegia (CPEO) caused by a mutation of the mitochondrial adenine nucleotide translocator 1 (ANT1, SLC25A4) implicated that ANT1 mutations confer a risk of BD. Here, we sequenced ANT1 in 324 probands of NIMH bipolar disorder pedigrees and identified two BD patients carrying heterozygous loss-of-function mutations. Behavioral analysis of brain specific Ant1 heterozygous conditional knockout (cKO) mice using lntelliCage showed a selective diminution in delay discounting. Delay discounting is the choice of smaller but immediate reward than larger but delayed reward and an index of impulsivity. Diminution of delay discounting suggests an increase in serotonergic activity. This finding was replicated by a 5-choice serial reaction time test. An anatomical screen showed accumulation of COX (cytochrome c oxidase) negative cells in dorsal raphe. Dorsal raphe neurons in the heterozygous cKO showed hyperexcitability, along with enhanced serotonin turnover in the nucleus accumbens and upregulation of Maob in dorsal raphe. These findings altogether suggest that mitochondrial dysfunction as the genetic risk of BD may cause vulnerability to BD by altering serotonergic neurotransmission.

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…Neuron‐specific adenine nucleotide translocator 1 ( Ant1 ) – another causative gene of CPEO – mutant mice showed impaired calcium uptake into mitochondria and hyper‐activation of dorsal raphe serotonergic neurons …”

“…Neuron-specific adenine nucleotide translocator 1 (Ant1)another causative gene of CPEOmutant mice showed impaired calcium uptake into mitochondria and hyper-activation of dorsal raphe serotonergic neurons. 145 Of note, there is a strong projection from the dorsal raphe to the PVT. The reason why these two structures are damaged by mitochondrial dysfunction is not yet known.…”

“…GWAS, genome-wide association studies; WGS, whole-genome sequencing. Trait-dependent alteration of 5-hydroxyindoleacetic acid 186 Hyperactivity of serotonergic neurons in Ant1 mutant mice 145 Atypical antipsychotics (5-HT antagonists) 263 Comorbidity with mitochondrial diseases [138][139][140] Recurrent depression-like episodes in Polg mice 143 Dietary supplements to improve mitochondrial function are under investigation 239…”

Cardiolipin is essential for early embryonic viability and mitochondrial integrity of neurons in mammals

“…27 In addition, down-regulation of CypD was observed in the brain of another mouse model of the disease. 27 In addition, down-regulation of CypD was observed in the brain of another mouse model of the disease.…”

“…27,28 Briefly, mitochondria of mouse brains (50-70 weeks old) were isolated using a discontinuous Percoll gradient. 27,28 Briefly, mitochondria of mouse brains (50-70 weeks old) were isolated using a discontinuous Percoll gradient.…”