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Published on: May 10, 2015
Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus
T Kasahara1, A Takata1, T M Kato1
1Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Abstract:
Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.
Insights
Researchers developed a new mouse model for depression by altering mitochondrial DNA polymerase (Polg1). This model shows depression-like symptoms and identifies the paraventricular thalamic nucleus (PVT) as a key brain area involved in mitochondrial dysfunction and mood disorders.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Psychiatry
Background:
- Depression is a widespread, debilitating condition with poorly understood causes.
- Animal models are crucial for studying depression but are challenging to develop.
- Mitochondrial dysfunction is increasingly implicated in various neurological and psychiatric disorders.
Purpose of the Study:
- To develop a novel preclinical model for major depressive episodes.
- To investigate the role of mitochondrial dysfunction in depression.
- To identify specific brain regions involved in depression pathogenesis.
Main Methods:
- Generated a transgenic mouse model with chronic forebrain expression of a dominant-negative mutant Polg1.
- Assessed behavioral changes, including emotional, vegetative, and psychomotor disturbances.
- Conducted a comprehensive screen of the mutant brain to identify sites of mitochondrial dysfunction.
- Utilized Cre-loxP-dependent expression of tetanus toxin to inhibit synaptic output in the paraventricular thalamic nucleus (PVT).
Main Results:
- The Polg1 mutant mice displayed lethargic behavior, resembling human depressive episodes and responding to antidepressant treatment.
- Mitochondrial DNA (mtDNA) deletions and dysfunction were concentrated in the paraventricular thalamic nucleus (PVT) of mutant brains.
- Similar mitochondrial defects were found in postmortem brains of patients with mitochondrial disease and mood symptoms.
- Inhibiting PVT synaptic output in mice induced de novo depression-like episodes.
Conclusions:
- A novel transgenic mouse model exhibiting depression-like symptoms has been established.
- Mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) is identified as a key cellular mechanism underlying depression.
- This study provides a new avenue for understanding and treating major depressive episodes.
