Highlights d Four mouse models of autism share a common increase in E-I ratio in sensory cortex d E-I ratio changes acted to stabilize synaptic depolarization and spiking d Sensory-evoked firing rate in vivo was remarkably normal and sometimes decreased d These findings suggest E-I ratio changes are compensatory in autism

Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly co-activated ensembles following contextual fear discrimination identified the Dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde mono-synaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context appropriate behavioral fear responses.