A depression-like phenotype is associated with discrete defects in the primary hippocampal circuit.

Major depressive disorder is known to disturb the hippocampus, but how this impacts signal processing performed by the structure remains poorly understood. Here, we report that single housing (7-10 days) promotes a depression-like phenotype in young adult mice that is associated with a robust, yet surprisingly discreet defect in information flow across the primary hippocampal circuit. In addition to sociability disturbances and despair-like behavior, single housing eliminated preference for novelty and impaired episodic memory encoding. Additionally, the lateral habenula, an epithalamic structure critically involved in depression, was hyperactive. Although the CA1 waveform and associated spike output elicited by single-pulse lateral perforant path (LPP) activation of hippocampus was largely unaffected by single housing, pronounced disturbances emerged when the circuit was activated with physiologically relevant frequencies and patterns. The characteristic 'theta/gamma' pattern was distorted such that a pronounced facilitation was present in the single-housed group, while the filtering of CA1 output to brief beta (25 Hz) and gamma (50 Hz) frequency LPP stimulation evident in group-housed slices was absent. Within field CA3, the recruitment of inhibitory interneurons suppresses spike output, and subsequent signal propagation to CA1, in response to beta frequency LPP inputs but not those arriving at gamma frequencies. This CA3 beta filter was significantly impaired following single housing. These results suggest that a depression phenotype is associated with a highly selective and partial loss of inhibition within the CA3 and CA1 links of the hippocampal circuit, providing new insights into the relationship between depression and hippocampal function.