title: Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex.
abstract: Akt is a serine/threonine kinase, which is dramatically reduced in the prefrontal cortex (PFC) of patients with schizophrenia, and a deficiency in Akt1 results in PFC function abnormalities. Although the importance of Akt in dopamine (DA) transmission is well established, how impaired Akt signaling affects the DA modulation of synaptic transmission in the PFC has not been characterized. Here we show that Akt inhibitors significantly decreased receptor sensitivity to DA by shifting DA modulation of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in prefrontal cortical neurons. Akt inhibition caused a significant decrease in synaptic dopamine D2 receptor (D2R) levels with high-dose DA exposure. In addition, Akt inhibition failed to affect DA modulation of IPSCs after blockade of β-arrestin 2. β-arrestin 2-mediated interaction of clathrin with D2R was enhanced by co-application of a Akt inhibitor and DA. Taken together, the reduced response in DA modulation of inhibitory transmission mainly involved β-arrestin 2-dependent D2R desensitization.
authors.affiliation: Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Yang
authors.affiliation: Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address: wgao@drexelmed.edu.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Gao
mesh_terms: D000818:Animals; D004298:Dopamine / Q000494:pharmacology*; D005260:Female; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000172:deficiency*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D017448:Receptors, Dopamine D2; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine
keywords: Akt; Dopamine; Dopamine receptors; Inhibitory synaptic transmission; Prefrontal cortex; Schizophrenia