Impaired Fluoxetine-Induced Post-Stroke Depression Recovery in a Protocadherin αc2 Deficient Mouse Model

Abstract

Post-stroke depression (PSD) occurs in 30-50% of stroke patients and is associated with poor recovery, stroke recurrence, and increased death rate. Chronic SSRI treatment can recover the PSD phenotype in mice, but the mechanism of regrowth remains largely unknown. This study aimed to uncover the importance of protocadherin-alphaC2 (pcdhαC2), the main protocadherin isoform found in serotonin neurons, in PSD recovery. Previous studies have shown that knocking out pcdhα in serotonin neurons caused brain-wide tangling of serotonin axons and a depression- like phenotype. Pcdhαc2 knockout mice were used to assess baseline innervation differences, and then stroke recovery with or without fluoxetine (FLX) treatment. Naïve pcdhαc2 knockout mice showed significantly impaired 5-HT innervation in the medial prefrontal cortex and hippocampus, with heterozygous knockout mice showing intermediate impairment. Stroke mice all exhibited significant anxiety and depression-like phenotypes post- stroke. Only wildtype mice properly recovered their depressive-like phenotype following FLX treatment, with only moderate recovery by heterozygous pcdhαc2 knockout mice. Stroke mice also had decreased 5-HT innervation in the medial prefrontal cortex and basolateral amygdala, with complete FLX-induced recovery only in the wildtype mice. Taken together, these results indicate that in PSD mice depleted of pcdhαc2, chronic FLX fails to reverse the PSD behavioural phenotype and recover 5-HT innervation in key brain regions. This implicates pcdhαc2 in PSD recovery and could elucidate new targets to enhance neuroplasticity for recovery post-stroke.