Background
Disrupted in schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar
disorder, major depressive disorder, and autism. To date, most of research examining
DISC1 function has focused on its role in neurodevelopment, despite its presence throughout
life. DISC1 also regulates cyclic adenosine monophosphate (cAMP) signaling by increasing
type 4 phosphodiesterase catabolism of cAMP when cAMP concentrations are high. In
this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates
I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate
the activity of mature prefrontal cortical pyramidal neurons.
Methods
We used patch-clamp recordings in prefrontal cortical slices from adult rats in which
DISC1 function was reduced in vivo by short hairpin RNA viral knockdown or in vitro
by dialysis of DISC1 antibodies.
Results
We found that DISC1 disruption resulted in an increase of metabotropic glutamate receptor-induced
intracellular calcium (Ca2+) waves, small-conductance K+ (SK)-mediated hyperpolarization and a decrease of transient receptor potential C
(TRPC)-mediated sustained depolarization. Consistent with a role for DISC1 in regulation
of cAMP signaling, forskolin-induced cAMP production also increased intracellular
Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine,
an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels.
Conclusions
Based on our findings, we propose that diminished DISC1 function, such as occurs in
some mental disorders, can lead to the disruption of normal patterns of prefrontal
cortex activity through the loss of cAMP regulation of metabotropic glutamate receptor-mediated
intracellular Ca2+ waves, SK and TRPC channel activity.
Key Words
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Article info
Publication history
Published online: January 22, 2014
Accepted:
December 30,
2013
Received in revised form:
December 22,
2013
Received:
January 7,
2013
Identification
Copyright
Published by Elsevier Inc.
