Cognitive impairments in mice after targeted perineuronal net depletion in the medial prefrontal or retrosplenial cortex.

Abstract

Perineuronal nets are highly organized components of the extracellular matrix which inhibit cellular plasticity and support cellular function. Depletion of perineuronal nets in rodents via developmental models of disease or via direct pharmacological interventions (e.g. chondroitinase) can impact cognitive function. In our current study, we utilized injections of an immune-evasive dual vector system, where the chondroitinase gene is under a doxycycline regulatory control, to induce bilateral secretion of chondroitinase, with temporal control, in the medial prefrontal cortex and retrosplenial cortex. These two brain regions are known to be involved in the function of working memory. We subjected mice to 30 days of activated chondroitinase-expression to deplete their perineuronal nets, followed by 30 days without to allow for a window of recovery. Prior to treatment, after treatment, and after 30 days without doxycycline-induced chondroitinase expression, animals were tested in a cross-modal object recognition task and an oddity task, which have been shown to be sensitive to manipulations of the medial prefrontal and retrosplenial cortex. Preliminary data indicates that controlled depletion of perineuronal nets in the medial prefrontal and retrosplenial cortex impacts performance of working memory. While there is some recovery in their working memory performance after 30 days without continuing enzymatic depletion, they do not recover to baseline behavioural performance. This data suggests that perineuronal net degradation in the medial prefrontal and retrosplenial cortex impacts working memory performance, and that these changes are long-lasting.