title: Too little and too much: hypoactivation and disinhibition of medial prefrontal cortex cause attentional deficits.
abstract: Attentional deficits are core symptoms of schizophrenia, contributing strongly to disability. Prefrontal dysfunction has emerged as a candidate mechanism, with clinical evidence for prefrontal hypoactivation and disinhibition (reduced GABAergic inhibition), possibly reflecting different patient subpopulations. Here, we tested in rats whether imbalanced prefrontal neural activity impairs attention. To induce prefrontal hypoactivation or disinhibition, we microinfused the GABA-A receptor agonist muscimol (C4H6N2O2; 62.5, 125, 250 ng/side) or antagonist picrotoxin (C30H34O13; 75, 150, 300 ng/side), respectively, into the medial prefrontal cortex. Using the five-choice serial reaction time (5CSRT) test, we showed that both muscimol and picrotoxin impaired attention (reduced accuracy, increased omissions). Muscimol also impaired response control (increased premature responses). In addition, muscimol dose dependently reduced open-field locomotor activity, whereas 300 ng of picrotoxin caused locomotor hyperactivity; sensorimotor gating (startle prepulse inhibition) was unaffected. Therefore, infusion effects on the 5CSRT test can be dissociated from sensorimotor effects. Combining microinfusions with in vivo electrophysiology, we showed that muscimol inhibited prefrontal firing, whereas picrotoxin increased firing, mainly within bursts. Muscimol reduced and picrotoxin enhanced bursting and both drugs changed the temporal pattern of bursting. Picrotoxin also markedly enhanced prefrontal LFP power. Therefore, prefrontal hypoactivation and disinhibition both cause attentional deficits. Considering the electrophysiological findings, this suggests that attention requires appropriately tuned prefrontal activity. Apart from attentional deficits, prefrontal disinhibition caused additional neurobehavioral changes that may be relevant to schizophrenia pathophysiology, including enhanced prefrontal bursting and locomotor hyperactivity, which have been linked to psychosis-related dopamine hyperfunction.
authors.affiliation: School of Psychology, Neuroscience@Nottingham, and marie.pezze@nottingham.ac.uk tobias.bast@nottingham.ac.uk.
authors.forename: Marie
authors.initials: M
authors.lastname: Pezze
authors.affiliation: School of Psychology, Neuroscience@Nottingham, and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: McGarrity
authors.affiliation: Neuroscience@Nottingham, and School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
authors.forename: Rob
authors.initials: R
authors.lastname: Mason
authors.affiliation: Neuroscience@Nottingham, and School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Fone
authors.affiliation: School of Psychology, Neuroscience@Nottingham, and marie.pezze@nottingham.ac.uk tobias.bast@nottingham.ac.uk.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bast
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000209:etiology* / Q000473:pathology*; D002755:Choice Behavior / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005074:Evoked Potentials, Visual / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010852:Picrotoxin / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects
chemical_list: D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D009118:Muscimol; D010852:Picrotoxin
keywords: attention; cognitive deficits; disinhibition; hypoactivation; in vivo electrophysiology; prefrontal cortex