title: Prefrontal cortical GABA modulation of spatial reference and working memory.
abstract: BACKGROUND
  Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear.
  
  
  METHODS
  We assessed the effects of pharmacological reduction of GABAA signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference. Male rats were well-trained to retrieve food from the same 4 arms of an 8-arm maze, receiving 5 trials/day (1-2 min intervals).
  
  
  RESULTS
  Infusions of the GABAA receptor antagonist bicuculline (12.5-50 ng) markedly increased working and reference memory errors and response latencies. Similar treatments also impaired short-term memory on an 8-baited arm task. These effects did not appear to be due to increased susceptibility to proactive interference. In contrast, PFC inactivation via infusion of GABA agonists baclofen/muscimol did not affect reference/working memory. In comparison to the pronounced effects on the 8-arm maze tasks, PFC GABAA antagonism only causes a slight and transient decrease in accuracy on a 2-arm spatial discrimination.
  
  
  CONCLUSIONS
  These findings demonstrate that prefrontal GABA hypofunction severely disrupts spatial reference and short-term memory and that disinhibition of the PFC can, in some instances, perturb memory processes not normally dependent on the frontal lobes. Moreover, these impairments closely resemble those observed in schizophrenic patients, suggesting that perturbation in PFC GABA signaling may contribute to these types of cognitive deficits associated with the disorder.
authors.affiliation: Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver BC, Canada (Drs Auger and Floresco).
authors.forename: Meagan L
authors.initials: ML
authors.lastname: Auger
authors.affiliation: Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver BC, Canada (Drs Auger and Floresco). floresco@psych.ubc.ca.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Floresco
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D009118:Muscimol / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D020318:Rats, Long-Evans; D011963:Receptors, GABA-A / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D001640:Bicuculline
keywords: GABA; prefrontal cortex; reference memory; schizophrenia; working memory.