Myo-Inositol Dampens Apathetic Symptoms in Aged Mice and Is Associated with Sex-Specific Synapse Remodelling

Late-life depression is associated with reduced treatment efficacy and age-related impairments in synaptic plasticity and stress responsiveness. Myo-inositol, an endogenous regulator of phosphoinositide signalling, has been proposed as candidate treatment for mood disorders, but its effects in age-related mood disorders remain unclear. Here, we investigated the impact of chronic myo-inositol supplementation on depressive behaviour and synaptic markers in aged male and female mice. Aged mice displayed reduced self-care behaviour in the sucrose splash test compared to young adults. Myo-inositol supplementation restored grooming behaviour in both sexes, an effect maintained following exposure to unpredictable chronic mild stress and independent of locomotor activity. Molecular analyses revealed sex-specific synaptic adaptations, with myo-inositol enhancing postsynaptic density protein 95 (PSD-95) levels in aged males, while increasing phosphorylation of the AMPA receptor subunit GluA1 at serine 845 and TARP expression in females. These findings demonstrate that myo-inositol dampens age-related apathetic alterations and is associated with sex-specific synaptic mechanisms, supporting its potential as a therapeutic strategy for late-life depression.