Aberrant Cortical Ensembles and Schizophrenia-like Sensory Phenotypes in Setd1a^+/- Mice

A breakdown of synchrony within neuronal ensembles leading to destabilization of network "attractors" could be a defining aspect of neuropsychiatric diseases such as schizophrenia, representing a common downstream convergence point for the diverse etiological pathways associated with the disease. Using a mouse genetic model, we demonstrated that altered ensembles are associated with pathological sensory cortical processing phenotypes resulting from loss of function mutations in the Setd1a gene, a recently identified rare risk genotype with very high penetrance for schizophrenia.

We used fast two-photon calcium imaging of neuronal populations (calcium indicator GCaMP6s, 10 Hz, 100-250 cells, layer 2/3 of primary visual cortex, i.e., V1) in awake head-fixed mice (Setd1a^+/- vs. wild-type littermate control) during rest and visual stimulation with moving full-field square-wave gratings (0.04 cycles per degree, 2.0 cycles per second, 100% contrast, 12 directions). Multielectrode recordings were analyzed in the time-frequency domain to assess stimulus-induced oscillations and cross-layer phase synchrony.

Neuronal activity and orientation/direction selectivity were unaffected in Setd1a^+/- mice, but correlations between cell pairs in V1 showed altered distributions compared with wild-type mice, in both ongoing and visually evoked activity. Furthermore, population-wide "ensemble activations" in Setd1a^+/- mice were markedly less reliable over time during rest and visual stimulation, resulting in unstable encoding of basic visual information. This alteration of ensembles coincided with reductions in alpha and high-gamma band phase synchrony within and between cortical layers.

These results provide new evidence for an ensemble hypothesis of schizophrenia and highlight the utility of Setd1a^+/- mice for modeling sensory-processing phenotypes.