L-alpha-amino adipic acid provokes depression-like behaviour and a stress related increase in dendritic spine density in the pre-limbic cortex and hippocampus in rodents

Astrocyte dysfunction is implicated in clinical depression. There is a paucity of animal models to assess the roleof astrocytes in depression pathogenesis. Refinement of an existing model is described here. Administration ofthe astrocytic toxin L-alpha aminoadipic acid (L-AAA) to the pre-limbic cortex (PLC) was assessed in rats andmice in tests of anxiety and depression related behaviours. Delivery of L-AAA to the PLC of Wistar rats producedan increase in immobility in the forced swimming test (FST) and reduced exploration in the openfield. Deliveryto the CA3 subfield of the hippocampus produced a deficit in the novel object relocation task. Delivery of singleor two successive doses of L-AAA to the PLC of C57Bl6/J mice was sufficient to induce an increase in immobilityin the mouse tail suspension (TST) and FST independently of administration of anaesthetic agent or the surgicalprocedure. In both mice and rats, L-AAA produced a reduction in immunoreactivity of the astrocytic marker glialfibrillary acidic protein (GFAP) for up to 72 h. L-AAA provoked an increase in the density of apical and basaldendritic spines in mice exposed to the FST when compared to non-FST controls. In summary, L-AAA provokes aregion-dependent change in behaviour, a reduction in GFAP immunoreactivity and FST-provoked increased indendritic spine density in the PLC. This model may be further employed to assess the impact of astroglialintegrity on the structural plasticity of neurons and the effect of antidepressant agents on L-AAA-related changes.