Differential proteomics analyses reveal anxiety-associated molecular and cellular mechanisms in cingulate cortex synapses

Selectively inbred animal models for anxiety traits provide useful insights for the elucidation of the relevant pathophysiological mechanisms of anxiety disorders by modeling molecular pathology in a defined genetic background. However, little is currently known about the functional characteristics that distinguish high anxiety-related (HAB) from low anxiety-related (LAB) behaviors. Analytical integration of cingulate cortex (CC) synaptosomal proteomes of HAB and LAB mice revealed that the synaptic environment in the cingulate cortex of HAB animals is dominated by the stabilization and enlargement of existing excitatory dendritic spines, associated with increased high-frequency stimulation of excitatory glutamatergic synapses, enhanced control over the modulation of synaptic strength and relatively weakened inhibitory GABAergic control together with increased spontaneous synaptic activity in non-glutamatergic network members. This is coupled with increased oxidative phosphorylation (OXPHOS), enhanced fatty acid oxidation and ATP production in synaptic mitochondria. The mitochondrial effects of increased oxidative and ionic stress appear to be controlled through at least seven different mechanisms, while the mechanisms attached to the maintenance of mitochondrial structural integrity and protein homeostasis are significantly reinforced. Overall, this analysis describes a context characterized by excitatory long-term potentiation (LTP) maintenance, low de novo spine generation, significant neurotransmission imbalances and structural as well as metabolic adaptations to persistent synaptic mitochondrial Ca 2+ loading and oxidative stress associated with the HAB phenotype