Mitochondrial OPA1 deficiency is associated to reversible defects in spatial memory related to adult neurogenesis in mice

Abstract

Mitochondria are integrative hubs central to cellular adaptive pathways. Such pathways are critical in highly differentiated post-mitotic neurons, the plasticity of which sustains brain function. Consequently, defects in mitochondria and in their dynamics appear instrumental in neurodegenerative diseases and may also participate in cognitive impairments. To directly test this hypothesis, we analyzed cognitive performances in a mouse mitochondria-based disease model, due to haploinsufficiency in the mitochondrial optic-atrophy-type-1 (OPA1) protein involved in mitochondrial dynamics. In males, we evaluated adult hippocampal neurogenesis parameters using immunohistochemistry. We performed a battery of tests to assess basal behavioral characteristics and cognitive performances, and tested putative treatments.

While in Dominant Optic Atrophy (DOA) mouse models, the known main symptoms are late onset visual deficits, we discovered early impairments in hippocampus-dependent spatial memory attributable to defects in adult neurogenesis. Moreover, less connected adult-born hippocampal neurons showed a decrease in mitochondrial content. Remarkably, voluntary exercise or pharmacological treatment targeting mitochondrial dynamics restored spatial memory in DOA mice. Altogether, our study identifies a crucial role for OPA1-dependent mitochondrial functions in adult neurogenesis, and thus in hippocampal-dependent cognitive functions. More generally, our findings show that adult neurogenesis is highly sensitive to mild mitochondrial defects, generating impairments in spatial memory that can be detected at an early stage and counterbalanced by physical exercise and pharmacological targeting of mitochondrial dynamics. Thus, amplification of mitochondrial function at an early stage appears beneficial for late-onset neurodegenerative diseases.

Significance Statement

The adult hippocampus continues to produce new neurons in mammals. These new neurons are highly sensitive to mitochondrial perturbation. Dominant optic atrophy (DOA) is a rare disease mainly caused by mutations in the gene coding the mitochondrial protein OPA1. Using a mouse model of OPA1 deficiency, we found that hippocampal new neurons have dendritic spine density defects and altered mitochondrial content. We further detected impairments in spatial memory capacities relying on adult-neurogenesis. We report that these memory impairments can be corrected by physical exercise and pharmacological treatment targeting mitochondria in mice. Our results indicate that early detection of spatial memory deficits related to adult neurogenesis may allow a precocious action in pathologies involving mitochondria, such as DOA or neurodegenerative diseases.