Depressive disorders and the treatment thereof have been associated with a number of neuroplastic events, such as neurogenesis and synaptic remodeling in discrete areas of the brain. The associations of these events in changes regarding the energy supply have not been investigated. Here, we investigated the changes in mitochondrial plasticity and its correlation to morphological alterations of neuroplasticity in the hippocampus, both associated with a depressive phenotype, and after treatment, with antidepressant imipramine. Design-based stereological methods were used to estimate the number and volume of mitochondria in CA1 of the hippocampus in two different strains of rats, the Sprague–Dawley (SD) and Flinders rats, which display a genetic susceptibility to depressive behavior, the Flinders-sensitive line (FSL) and their corresponding controls, the Flinders-resistant line (FRL). Results showed a significantly reduced number of mitochondria in CA1, which was significantly smaller in the untreated FSL saline group compared to the FRL group. However, the mean volume of mitochondria was significantly larger in the FSL saline group compared to the FRL saline group. Following treatment, the FSL imipramine group showed a significant increase in the number of mitochondria compared to the FSL saline group. Treatment with imipramine in the SD rats did not induce significant differences in the number of mitochondria. Our results indicate that depression may be related to impairments of mitochondrial plasticity in the hippocampus and antidepressant treatment may counteract with the structural impairments. Moreover, the changes in mitochondrial morphology and number are a consistent feature of neuroplasticity. Synapse, 2013. © 2012 Wiley Periodicals, Inc.