Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

Abstract

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 regulate cAMP signaling by increasing PDE4 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 shRNA viral knockdown or in vitro by dialysis of DISC1 antibodies. Results We found that DISC1 disruption resulted in an increase of: mGluR-induced intracellular Ca2+ waves, SK-mediated hyperpolarization and a decrease of 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 PFC activity through the loss of cAMP regulation of mGluR-mediated intracellular Ca2+ waves, SK and TRPC channel activity.

Stress weakens prefrontal networks: molecular insults to higher cognition

“…Knockdown of DISC1 in rodent PFC increases cAMP signaling in PFC neurons 129 and increases sensitivity to stress-induced PFC cognitive deficits 130 . DISC1 also regulates the integrity of PFC spines by anchoring kalirin-7 (Kal7, the rodent homolog of Duo) and preventing its stimulation of Rac1 signaling 131 .…”

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.…”

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.…”