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Schizophrenia Bulletin Advance Access originally published online on July 26, 2007
Schizophrenia Bulletin 2007 33(6):1284-1290; doi:10.1093/schbul/sbm088
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© The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org.

Schizophrenia, Hypocretin (Orexin), and the Thalamocortical Activating System

Evelyn K. Lambe1,2, Rong-Jian Liu3 and George K. Aghajanian3,4
2 Department of Physiology, University of Toronto, Toronto, Canada
3 Departments of Psychiatry and
4 Department of Pharmacology, Yale School of Medicine, New Haven, CT

1 To whom correspondence should be addressed; email: evelyn.lambe{at}utoronto.ca

Diminished connectivity between midline-intralaminar thalamic nuclei and prefrontal cortex has been suggested to contribute to cognitive deficits that are detectable even in early stages of schizophrenia. The midline-intralaminar relay cells comprise the final link in the ascending arousal pathway and are selectively excited by the wake-promoting peptides hypocretin 1 and 2 (orexin A and B). This excitation occurs both at the level of the relay cell bodies and their axon terminals within prefrontal cortex. In rat brain slices, the release of glutamate from midline-intralaminar thalamocortical terminals induces excitatory postsynaptic currents (EPSCs) in layer V pyramidal cells in prefrontal cortex. When hypocretin is infused into medial prefrontal cortex of behaving animals, it improves performance in a complex cognitive task requiring divided attention. Chronic restraint stress causes atrophy of the apical dendritic arbors in layer V prefrontal pyramidal cells and leads to a reduction in hypocretin-induced EPSCs, indicating impairment in excitatory thalamocortical transmission. Thus, taken together with evidence for an underlying loss of excitatory thalamocortical connectivity in schizophrenia, stress in this illness could further exacerbate a breakdown in cortical processing of incoming information from the ascending arousal system.

Keywords: attention / dendrite / EPSC / prefrontal / stress


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