Abstract
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.
Highlights
Psychiatric disorders such as schizophrenia involve profound dysfunction of the prefrontal cortex (PFC).[1,2,3,4,5,6] The PFC uses working memory to provide top-down modulation of behavior, thought and affect[7,8,9], and its function is weakened by exposure to even mild, uncontrollable stress.[10]
We primarily focused on disrupted in schizophrenia 1 (DISC1) expression in dendrites, as we were interested in its role in modulating the connectivity of PFC networks at dendritic spines
Summary of findings In this study, we have demonstrated that reducing DISC1 function in PFC increased vulnerability to the impairing effects of acute stress on working memory performance
Summary
Psychiatric disorders such as schizophrenia involve profound dysfunction of the prefrontal cortex (PFC).[1,2,3,4,5,6] The PFC uses working memory to provide top-down modulation of behavior, thought and affect[7,8,9], and its function is weakened by exposure to even mild, uncontrollable stress.[10]. It is critical to understand the molecular influences that modulate PFC function during stress in order to develop intelligent medications for psychiatric disorders. Generation of cyclic adenosine monophosphate (cAMP) increases the open state of nearby potassium channels in dendritic spines, for example, hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels,[18,19] and reduces network firing. This mechanism allows for rapid flexibility in sculpting the contents of working memory, it is vulnerable to a variety of genetic and environmental insults, for example, in psychiatric disorders and during stress. Increased release of catecholamines in PFC during even mild stress exposure increases cAMP signaling, which reduces PFC neuronal firing and impairs working memory.[11]
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