Dsg2 arrhythmogenic cardiomyopathy is accompanied by neocortical synaptic changes in adult mice

Abstract Heart failure is frequently accompanied by cognitive impairment, yet structural correlates in the brain remain incompletely defined. Here, we assessed whether chronic heart failure is associated with synaptic ultrastructural remodeling in the murine neocortex using a mouse model of arrhythmogenic cardiomyopathy caused by a point mutation in desmoglein-2 (Dsg2-W2A). Brains from aged adult homozygous Dsg2-W2A mice and age-matched wildtype controls were processed for transmission electron microscopy, and excitatory synapses in layer I of the prefrontal cortex were quantitatively assessed, with comparative analyses in the somatosensory cortex. In the prefrontal cortex, presynaptic terminal area and synaptic vesicle number were reduced in mutant mice, whereas postsynaptic measures were not altered. The prevalence of mitochondria and the spine apparatus within synapses was comparable between genotypes, suggesting no major loss of synapse-associated organelles. Finally, synaptic parameters in the prefrontal cortex did not show a systematic dependence on distance to local blood vessels. Together, these findings indicate moderate region- and compartment-specific synaptic ultrastructural alterations associated with Dsg2 cardiomyopathy and chronic heart failure, with predominant effects on presynaptic terminals.