Abstract
Altered social behaviors are prevalent in neurodevelopmental disorders like monogenic Rett syndrome, which is caused by pathogenic variants in the gene encoding the methylated DNA binding transcriptional regulator MeCP2. Monosynaptic projections from the ventral hippocampus to the medial prefrontal cortex (mPFC) modulate social memory, and are altered in male Mecp2 knockout (KO) mice. The standard tube test was used to define the social hierarchy between age- and genotype-matched triads over six consecutive days of round-robin competitions, and revealed that male Mecp2 KO mice form social ranks but display more submissive behaviors than those observed between similarly aged triads of male wild-type (WT) littermate controls. The same triads of each genotype performed similarly in the warm spot test, where mice of each genotype compete to stand on a single warm spot in a cage with a cooled floor. The dominant WT mouse from the prior tube test had preferential and active access to the beneficial place in the competition test (warm spot) showing more dominant behaviors than the other two WT mice. On the contrary, all three Mecp2 KO mice shared the warm spot equally, showing more submissive behaviors than those observed between the three WT mice. In vivo Ca2+ imaging from pyramidal neurons in the prelimbic mPFC during the warm spot test confirmed the presence of socially sensitive neurons, i.e., neurons that either increase or decrease their spiking activity during social interactions. mPFC pyramidal neurons in male Mecp2 KO mice showed fewer and smaller Ca2+ transients during baseline, as well as during each social interaction in the warm spot test, when their activity is less synchronous than in those of WT mice. In addition, chronically inhibiting the activity of mPFC-projecting excitatory neurons of the ventral hippocampus using an intersectional DREADD approach restored behavioral deficits in male Mecp2 KO mice. Together, these results demonstrate that male Mecp2 mice show a low behavioral engagement during social competition tests that alters their social hierarchy and is reflected in altered activity and synchrony between mPFC pyramidal neurons. Our observations also underscore the potential relevance of this long-range projection for altered social behaviors in other mouse models of neurodevelopmental disorders associated with autism.