Destruction and Creation of Spatial Tuning by Disinhibition: GABA_ABlockade of Prefrontal Cortical Neurons Engaged by Working Memory

Abstract

Local circuit neurons in the dorsolateral prefrontal cortex (dPFC) of monkeys have been implicated in the cellular basis of working memory. To further elucidate the role of inhibition in spatial tuning, we iontophoresed bicuculline methiodide (BMI) onto functionally characterized neurons in the dPFC of monkeys performing an oculomotor delayed response task. This GABA(A) blockade revealed that both putative interneurons and pyramidal cells possess significant inhibitory tone in the awake, behaving monkey. In addition, BMI application primarily resulted in the loss of previously extant spatial tuning in both cell types through reduction of both isodirectional and cross-directional inhibition. This tuning loss occurred in both the sensorimotor and mnemonic phases of the task, although the delay activity of prefrontal neurons appeared to be particularly affected. Finally, application of BMI also created significant spatial tuning in a sizable minority of units that were untuned in the control condition. Visual field analysis of such tuning suggests that it is likely caused by the unmasking of normally suppressed spatially tuned excitatory input. These findings provide the first direct evidence of directional inhibitory modulation of pyramidal cell and interneuron firing in both the mnemonic and sensorimotor phases of the working memory process, and they implicate a further role for GABAergic interneurons in the construction of spatial tuning in prefrontal cortex.

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

“…In primates and rodents, the delay in achieving mature performance on executive function tasks correlates with the maturation of oscillatory activity in the gamma range and with the maturation of PV-interneuronal networks (Wilson et al, 1994;Rao et al, 2000;Doischer et al, 2008;Uhlhaas et al, 2009), consistent with the delayed maturation of PV-inhibitory circuits. Development of PV-synaptic contacts, which sculpt this inhibitory network throughout childhood and adolescence, is dependent on GAD67 synthesis and activity in rodents (Chattopadhyaya et al, 2007).…”

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

“…Thus, these two different subtypes of prefrontal interneurons may contribute to different prefrontal functions mediated by circuits of the dlPFC and ORB. For example, GABA-mediated inhibition in the dlPFC has been shown to be an important element of working memory (Constantinidis and GoldmanRakic, 2002;Rao et al, 2000;Sawaguchi et al, 1989;Wilson et al, 1994). GABAergic abnormalities in the ORB have been suggested to be involved in psychomotor retardation, disinhibition, and obsessive-compulsive behavior (Bechara et al, 2000;Cummings, 1993;Volkow and Fowler, 2000).…”

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

“…It can readily be appreciated that similar neurons located in associative cortical regions may help to define the nature and integrity of higher cognitive functions, such as motivation, attention, learning and object recognition. For example, recent findings suggest a role for cortical interneurons in working memory (Wilson et al 1994;Rao et al 1999Rao et al , 2000. In the dorsal prefrontal cortex, 'fast spiking' interneurons have been shown to play an important role in shaping 'spatial memory fields' much in the same way as they have been found to shape 'sensory receptive fields' (Rao et al 1999(Rao et al , 2000.…”

“…For example, recent findings suggest a role for cortical interneurons in working memory (Wilson et al 1994;Rao et al 1999Rao et al , 2000. In the dorsal prefrontal cortex, 'fast spiking' interneurons have been shown to play an important role in shaping 'spatial memory fields' much in the same way as they have been found to shape 'sensory receptive fields' (Rao et al 1999(Rao et al , 2000. In addition, blockade of GABAergic inhibition in the inferotemporal area has been associated with a disruption of the normal response of neurons selective for particular object features .…”