title: Hippocampal place cell and inhibitory neuron activity in disrupted-in-schizophrenia-1 mutant mice: implications for working memory deficits.
abstract: BACKGROUND
  Despite the prevalence of working memory deficits in schizophrenia, the neuronal mechanisms mediating these deficits are not fully understood. Importantly, deficits in spatial working memory are identified in numerous mouse models that exhibit schizophrenia-like endophenotypes. The hippocampus is one of the major brain regions that actively encodes spatial location, possessing pyramidal neurons, commonly referred to as 'place cells', that fire in a location-specific manner. This study tests the hypothesis that mice with a schizophrenia-like endophenotype exhibit impaired encoding of spatial location in the hippocampus.
  
  
  OBJECTIVE
  To characterize hippocampal place cell activity in mice that exhibit a schizophrenia-like endophenotype.
  
  
  METHODS
  We recorded CA1 place cell activity in six control mice and six mice that carry a point mutation in the disrupted-in-schizophrenia-1 gene (Disc1-L100P) and have previously been shown to exhibit deficits in spatial working memory.
  
  
  RESULTS
  The spatial specificity and stability of Disc1-L100P place cells were similar to wild-type place cells. Importantly, however, Disc1-L100P place cells exhibited a higher propensity to increase their firing rate in a single, large location of the environment, rather than multiple smaller locations, indicating a generalization in their spatial selectivity. Alterations in the signaling and numbers of CA1 putative inhibitory interneurons and decreased hippocampal theta (5-12 Hz) power were also identified in the Disc1-L100P mice.
  
  
  CONCLUSIONS
  The generalized spatial selectivity of Disc1-L100P place cells suggests a simplification of the ensemble place codes that encode individual locations and subserve spatial working memory. Moreover, these results suggest that deficient working memory in schizophrenia results from an impaired ability to uniquely code the individual components of a memory sequence.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Lia
authors.identifier: 0000-0002-3197-6407
authors.initials: L
authors.lastname: Mesbah-Oskui
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto, ON, Canada.
authors.forename: John
authors.identifier: 0000-0003-4503-6384
authors.initials: J
authors.lastname: Georgiou
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Roder