Editors' ChoiceSchizophrenia

Working memory: The real VIP

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Science Translational Medicine  10 May 2017:
Vol. 9, Issue 389, eaan3779
DOI: 10.1126/scitranslmed.aan3779

Abstract

Interneurons expressing VIP may play a causal role in working memory.

Schizophrenia is a debilitating psychiatric illness characterized by hallucinations, delusions, impoverished speech, anhedonia, and a number of cognitive deficits, including loss of working memory. It has been a major challenge to develop treatments that ameliorate cognitive symptoms, at least in part due to a limited understanding of the neurobiological mechanisms that underlie normal cognition.

Multiple prior human imaging studies have implicated the prefrontal cortex in functional working memory, and deficits in the prefrontal cortex have been described in individuals with schizophrenia. At the cellular level, the firing of excitatory neurons in the prefrontal cortex has been linked to normal working memory, and altered firing of prefrontal cortex inhibitory neurons has been proposed to underlie schizophrenia-related working memory deficits. Nevertheless, the role of the diverse subtypes of inhibitory neurons in the prefrontal cortex that mediate working memory has not yet been causally established.

In a new study, Kamigaki and Dan use real-time calcium imaging to monitor the activity of prefrontal cortex excitatory neurons in a working memory task. In this task, mice were trained to initiate or inhibit a delayed behavioral choice in response to presentation of a sensory cue. Consistent with prior studies in nonhuman primates, the authors found that excitatory neurons fired reliably during the delay interval between the cue and the behavioral choice. Interestingly, direct activation of prefrontal cortex excitatory neurons using optogenetics impaired performance on the working memory task. Indirectly inhibiting these excitatory neurons by directly stimulating somatostatin-positive or parvalbumin-positive interneurons suppressed working memory performance as well. These findings suggested that the broad manipulation of prefrontal cortex excitatory neurons may be an ineffective strategy for improving working memory.

On the other hand, stimulating interneurons expressing vasoactive intestinal peptide (VIP) enhanced neural encoding by prefrontal cortex excitatory neurons and improved working memory performance. After demonstrating that inhibiting the VIP-positive interneurons impaired working memory, the authors verified that stimulating VIP-positive interneurons was sufficient to enhance working memory in an independent delayed sample-to-match test. By establishing a causal role for VIP-positive prefrontal cortex interneurons for mediating working memory, the authors highlight a new biological target for developing therapeutics to improve working memory in schizophrenia.

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