title: 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 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.
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut. Electronic address: lynda.elhassar@yale.edu.
authors.forename: Lynda
authors.initials: L
authors.lastname: El-Hassar
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Simen
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Duque
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Kiran D
authors.initials: KD
authors.lastname: Patel
authors.affiliation: Department of Pharmacology , Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Leonard K
authors.initials: LK
authors.lastname: Kaczmarek
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut; The Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Amy F T
authors.initials: AF
authors.lastname: Arnsten
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut; The Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Yeckel
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D000242:Cyclic AMP / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D015398:Signal Transduction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: C498795:Disc1 protein, rat; D009419:Nerve Tissue Proteins; D018094:Receptors, Metabotropic Glutamate; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D000242:Cyclic AMP
keywords: Ca(2) waves; DISC1; IP3; mGluR5; persistent activity; prefrontal cortex