Optogenetic induction of the schizophrenia-related endophenotype of ventral hippocampal hyperactivity causes rodent correlates of positive and cognitive symptoms

Amy R. Wolff, Alexei M. Bygrave, David J. Sanderson, Edward S. Boyden, David M. Bannerman, Dimitri M. Kullmann, Dennis Kätzel

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Pathological over-activity of the CA1 subfield of the human anterior hippocampus has been identified as a potential predictive marker for transition from a prodromal state to overt schizophrenia. Psychosis, in turn, is associated with elevated activity in the anterior subiculum, the hippocampal output stage directly activated by CA1. Over-activity in these subfields may represent a useful endophenotype to guide translationally predictive preclinical models. To recreate this endophenotype and study its causal relation to deficits in the positive and cognitive symptom domains, we optogenetically activated excitatory neurons of the ventral hippocampus (vHPC; analogous to the human anterior hippocampus), targeting the ventral subiculum. Consistent with previous studies, we found that vHPC over-activity evokes hyperlocomotion, a rodent correlate of positive symptoms. vHPC activation also impaired performance on the spatial novelty preference (SNP) test of short-term memory, regardless of whether stimulation was applied during the encoding or retrieval stage of the task. Increasing dopamine transmission with amphetamine produced hyperlocomotion, but was not associated with SNP impairments. This suggests that short-term memory impairments resulting from hippocampal over-activity likely arise independently of a hyperdopaminergic state, a finding that is consistent with the pharmaco-resistance of cognitive symptoms in patients.

Original languageEnglish (US)
Article number12871
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was funded by a Roche Postdoctoral Fellowship (RPF 247) awarded to A.R.W., D.K. and D.M.K. A.M.B. (OXION fellowship) and D.K. (Grant# 098896) were funded by fellowships from the Wellcome Trust. We thank Amy Taylor, the NACWOs, N.V.S. and B.M.S. staff at the University of Oxford for their assistance. We also thank Mark Walton, Stephen McHugh, Brian Allen, Tom Davidson, Marios Panagi, and Natalie Doig for technical advice.

Publisher Copyright:
© 2018, The Author(s).

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