Mitochondrial OPA1 deficiency causes reversible defects in adult neurogenesis-associated spatial memory in mice

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 mitochondrial dynamics and quality control 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. While in Dominant Optic Atrophy (DOA) 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 hippocampal adult-born neurons showed a decrease in mitochondrial content. Remarkably, modulating mitochondrial function through voluntary exercise or pharmacological treatment restored spatial memory. 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, early amplification of mitochondrial function appears beneficial for late-onset neurodegenerative diseases. ### Competing Interest Statement The authors have declared no competing interest. * BrdU : 5’-Bromo-2 deoxyuridine DCX : Doublecortine DAB : di-amino-Benzidine DMSO : Dimethyl sulfoxide DOA : Dominant optic atrophy Mdivi-1 : Mitochondrial division inhibitor 1 PB : Phosphate buffer PBST : Phosphate-buffered saline with Tween 20 PFA : Paraformaldehyde OPA1 : Optic atrophy type 1 protein RGCs : Retinal ganglion cells