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 (C 4 H 6 N 2 O 2 ; 62.5, 125, 250 ng/side) or antagonist picrotoxin (C 30 H 34 O 13 ; 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.

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…In the present study, hippocampal neural disinhibition did not affect response control on the 5CSRT test (as reflected by unchanged premature or perseverative responses), which has been shown to be markedly disrupted by both prefrontal and hippocampal lesions and/or inactivation (Chudasama and Robbins 2006;Chudasama et al 2012;Abela et al 2013;Pezze et al 2014); similar to hippocampal neural disinhibition, prefrontal disinhibition also does not affect response control ). This suggests that response control requires neural activity within the hippocampo-prefrontal circuit, but not the appropriate tuning of such activity.…”

“…In contrast, hippocampal neural disinhibition caused by picrotoxin in the present study altered the temporal organization of hippocampal neural activity (enhancing burst-pattern firing). Overall, hippocampus-dependent memory performance appears to require hippocampal neural activity that is appropriately balanced by GABAergic inhibition, resembling the requirement of appropriately tuned prefrontal activity for prefrontal-dependent cognitive functions (Gruber et al 2010;Pezze et al 2014;Tse et al 2015).…”

“…This has recently been established for prefrontal GABA dysfunction (Gruber et al 2010;Enomoto et al 2011;Paine et al 2011;Pehrson et al 2013;Pezze et al 2014;Paine et al 2015;Tse et al 2015), and there is also evidence linking hippocampal neural disinhibition and overactivity to impaired hippocampus-dependent memory performance (Koh et al 2010;Murray et al 2011;Andrews-Zwilling et al 2012;Bakker et al 2012 ;Caputi et al 2012;Gilani et al 2014;Lovett-Barron et al 2014). Moreover, regional disinhibition, by causing aberrant drive of projections, may disrupt neural activity and cognitive processing in distal sites.…”

“…To test if hippocampal neural disinhibition disrupts hippocampus-dependent memory and prefrontal-dependent attention, we combined hippocampal neural disinhibition by local microinfusion of the GABA-A antagonist picrotoxin Pezze et al 2014) with translational tests of clinically relevant cognitive deficits in rats. Infusions targeted temporal (also referred to as ventral) to intermediate hippocampus, because this part of the hippocampus features strong hippocampo-prefrontal connectivity and corresponds to human anterior hippocampus, which has been implicated in schizophrenia (Bast 2011).…”

Differential Pharmacological Regulation of Sensorimotor Gating Deficit in CB1 Knockout Mice and Associated Neurochemical and Histological Alterations

“…Cortical disinhibition is associated to preattentional deficits that are core symptoms of schizophrenia (Glausier et al, 2014;Lewis, 2014;Pezze et al, 2014;Volk and Lewis, 2014). However, recently altered GABAergic gene expression in ADHD children has also been reported (Wang et al, 2012), and alterations in PV-immunoreactive (PV-ir) neurons have been found in hypothyroid rats (Berbel et al, 1996), in humans suffering from epilepsy (DeFelipe, 2004), and in ASD patients (Berbel et al, 2014;Stoner et al, 2014).…”