Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction

Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure...

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Main Authors:	Gamo, N J, Duque, A, Paspalas, C D, Kata, A, Fine, R, Boven, L, Bryan, C, Lo, T, Anighoro, K, Bermudez, L, Peng, K, Annor, A, Raja, A, Mansson, E, Taylor, S R, Patel, K, Simen, A A, Arnsten, A F T
Format:	Online
Language:	English
Published:	Nature Publishing Group 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030323/

id	pubmed-4030323
recordtype	oai_dc
spelling	pubmed-40303232014-05-28 Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction Gamo, N J Duque, A Paspalas, C D Kata, A Fine, R Boven, L Bryan, C Lo, T Anighoro, K Bermudez, L Peng, K Annor, A Raja, A Mansson, E Taylor, S R Patel, K Simen, A A Arnsten, A F T Original Article Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing cAMP levels. The current study examined whether viral knockdown (KD) of the Disc1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down Disc1 in PFC (DISC1 KD group), (b) a ‘scrambled' construct that had no effect on Disc1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1 h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down Disc1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited cAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress. Nature Publishing Group 2013-12 2013-12-03 /pmc/articles/PMC4030323/ /pubmed/24301646 http://dx.doi.org/10.1038/tp.2013.104 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Gamo, N J Duque, A Paspalas, C D Kata, A Fine, R Boven, L Bryan, C Lo, T Anighoro, K Bermudez, L Peng, K Annor, A Raja, A Mansson, E Taylor, S R Patel, K Simen, A A Arnsten, A F T
spellingShingle	Gamo, N J Duque, A Paspalas, C D Kata, A Fine, R Boven, L Bryan, C Lo, T Anighoro, K Bermudez, L Peng, K Annor, A Raja, A Mansson, E Taylor, S R Patel, K Simen, A A Arnsten, A F T Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
author_facet	Gamo, N J Duque, A Paspalas, C D Kata, A Fine, R Boven, L Bryan, C Lo, T Anighoro, K Bermudez, L Peng, K Annor, A Raja, A Mansson, E Taylor, S R Patel, K Simen, A A Arnsten, A F T
author_sort	Gamo, N J
title	Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
title_short	Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
title_full	Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
title_fullStr	Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
title_full_unstemmed	Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction
title_sort	role of disrupted in schizophrenia 1 (disc1) in stress-induced prefrontal cognitive dysfunction
description	Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing cAMP levels. The current study examined whether viral knockdown (KD) of the Disc1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down Disc1 in PFC (DISC1 KD group), (b) a ‘scrambled' construct that had no effect on Disc1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1 h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down Disc1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited cAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress.
publisher	Nature Publishing Group
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030323/
_version_	1612092093370466304

Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction

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