Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning
Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABAA receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output. To test this, we assessed whether PFC GABAA antagonism (50 ng bicuculline methbromide) alters neuronal activation in PFC terminal regions, including the striatum, thalamus, hippocampus, amygdala, and cortical regions, of adult male rats using the immediate early gene, c-Fos, as an activity marker. A subset of these animals were also trained and/or tested on the working/reference memory radial maze task. These treatments caused widespread increases in neuronal activation in animals under baseline conditions, with notable exception of the hippocampus. Furthermore, PFC GABAA antagonism impaired task performance. In most instances, training and/or testing on the radial maze had no additional effects on neuronal activation. However, in both the hippocampus and rhomboid thalamic nucleus, PFC GABAA antagonism caused a selective increase in neuronal activation in animals trained on the maze. These results indicate that deficiencies in PFC GABAergic transmission may have widespread impacts on neuronal activity that may interfere with certain PFC-independent cognitive functions. Furthermore, these alterations in activity are modulated by plasticity induced by spatial learning in the hippocampus and rhomboid thalamic nucleus.
KeywordsPrefrontal cortex Hippocampus Schizophrenia GABA cFos Spatial memory Experience-dependent plasticity
This work was supported by a grant from the Canadian Institutes of Health Research (MOP 130393) to SBF. We thank Stephanie Lieblich and Paula Duarte-Guterman for their technical guidance in conducting these experiments.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All applicable international, national and/or institutional guidelines for the care and use of animals were followed.
Research involving human and/or animal participants
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.
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