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

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.

Neuroglial Transmission

“…cAMP control mechanisms enable flexible modulation of network strength, but when dysregulated, may result in mental disorders, including schizophrenia, bipolar disorder, autism, and age-or stress-dependent cognitive impairment (105,132), and even neurodegeneration such as in AD (59). Lactate gliotransmitter signaling via HCAR1, with its widespread distribution in brain regions and in neurons as well as glia (213), is positioned to contribute to optimizing the local cAMP concentration.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Furthermore, GAD1 suppression in CCK þ /CNR1 þ interneurons leads to dysfunctional amygdala-dependent behavior and aminergic signaling Schmidt et al, 2013). Finally, mild stress during development results in epigenetic-mediated reduction of dopaminergic cell function in DISC1 mutant mice (Niwa et al, 2013), whereas the loss of DISC1 in the frontal cortex of adult rats increased stress sensitivity and resulted in cognitive impairments that were not observed in rats with normal DISC1 expression (Gamo et al, 2013). These results establish an important G Â E interaction between DISC1 and stress and reinforce the importance of developmental timing of this interaction.…”

mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions

“…42 Schizophrenia is associated with insults to glutamate NMDAR actions 43,44 and with disinhibited cAMP signaling, for example, disrupted in schizophrenia 1 would anchor phosphodiesterase 4A in dlPFC spines, positioned to regulate the positive feedback cycle of cAMP-PKAcalcium signaling. 45,46 Insults to disrupted in schizophrenia 1 and phosphodiesterase 4A are linked to increased risk of illness. 47,48 Importantly, genetic alterations in mGluR3 are increasingly linked to schizophrenia, [8][9][10][11][12][13][14][15][16][17][18][19][20][21] including altered dlPFC activation and poorer cognitive performance.…”