The anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive compared to healthy controls. In rodent models of schizophrenia etiology, the ventral hippocampus, analogous to the human anterior hippocampus, is also hyperactive with effects on extrahippocampal neural circuits that might contribute to positive, negative, and cognitive symptoms. Less is known about how anterior hippocampal hyperactivity might directly influence intrahippocampal function across the structure’s longitudinal axis. This question is important for understanding cognitive dysfunction in schizophrenia, which includes deficits attributed to both the anterior and posterior hippocampus. We hypothesized that hyperactivity of ventral hippocampal mossy cells, which send dense longitudinal projections throughout the hippocampal longitudinal axis, may be sufficient to disrupt spatial memory encoding, a dorsal hippocampal-dependent function. Using an intersectional viral strategy, we targeted ventral mossy cells projecting to the dorsal dentate gyrus. In vivo fiber photometry revealed these cells were activated during behavior related to context mapping but not during non-exploratory motor behaviors. Anterograde transsynaptic tracing and optogenetic terminal stimulation revealed functional connectivity between ventral mossy cells and dorsal dentate gyrus granule cells. Finally, chemogenetic activation of ventral mossy cells during the encoding phase of an object location memory task impaired retrieval 24 hours later, without effects on locomotion or other exploratory behaviors. These findings suggest that anterior hippocampal hyperactivity may have intrahippocampal consequences to degrade posterior hippocampal function and support future studies engaging this circuit target to mitigate specific cognitive deficits associated with schizophrenia.
bioRxiv Subject Collection: Neuroscience