title: New model of action for mood stabilizers: phosphoproteome from rat pre-frontal cortex synaptoneurosomal preparations.
abstract: BACKGROUND
  Mitochondrial short and long-range movements are necessary to generate the energy needed for synaptic signaling and plasticity. Therefore, an effective mechanism to transport and anchor mitochondria to pre- and post-synaptic terminals is as important as functional mitochondria in neuronal firing. Mitochondrial movement range is regulated by phosphorylation of cytoskeletal and motor proteins in addition to changes in mitochondrial membrane potential. Movement direction is regulated by serotonin and dopamine levels. However, data on mitochondrial movement defects and their involvement in defective signaling and neuroplasticity in relationship with mood disorders is scarce. We have previously reported the effects of lithium, valproate and a new antipsychotic, paliperidone on protein expression levels at the synaptic level.
  
  
  OBJECTIVE
  Mitochondrial function defects have recently been implicated in schizophrenia and bipolar disorder. We postulate that mood stabilizer treatment has a profound effect on mitochondrial function, synaptic plasticity, mitochondrial migration and direction of movement.
  
  
  METHODS
  Synaptoneurosomal preparations from rat pre-frontal cortex were obtained after 28 daily intraperitoneal injections of lithium, valproate and paliperidone. Phosphorylated proteins were identified using 2D-DIGE and nano LC-ESI tandem mass spectrometry.
  
  
  RESULTS
  Lithium, valproate and paliperidone had a substantial and common effect on the phosphorylation state of specific actin, tubulin and myosin isoforms as well as other proteins associated with neurofilaments. Furthermore, different subunits from complex III and V of the electron transfer chain were heavily phosphorylated by treatment with these drugs indicating selective phosphorylation.
  
  
  CONCLUSIONS
  Mood stabilizers have an effect on mitochondrial function, mitochondrial movement and the direction of this movement. The implications of these findings will contribute to novel insights regarding clinical treatment and the mode of action of these drugs.
authors.affiliation: Neuropsycopharmacology Laboratory, Mayo Clinic, Jacksonville, Florida, USA. pilarcorena@gmail.com
authors.forename: Maria
authors.initials: M
authors.lastname: Corena-McLeod
authors.forename: Consuelo
authors.initials: C
authors.lastname: Walss-Bass
authors.forename: Alfredo
authors.initials: A
authors.lastname: Oliveros
authors.forename: Andres
authors.initials: A
authors.lastname: Gordillo Villegas
authors.forename: Carolina
authors.initials: C
authors.lastname: Ceballos
authors.forename: Cristine M
authors.initials: CM
authors.lastname: Charlesworth
authors.forename: Benjamin
authors.initials: B
authors.lastname: Madden
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Linser
authors.forename: Leslie
authors.initials: L
authors.lastname: Van Ekeris
authors.forename: Kristin
authors.initials: K
authors.lastname: Smith
authors.forename: Elliott
authors.initials: E
authors.lastname: Richelson
mesh_terms: D000199:Actins / Q000378:metabolism; D000339:Affect / Q000187:drug effects*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D007555:Isoxazoles / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000068882:Paliperidone Palmitate; D010750:Phosphoproteins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology*; D020543:Proteome / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000199:Actins; D014150:Antipsychotic Agents; D007555:Isoxazoles; D010750:Phosphoproteins; D020543:Proteome; D011743:Pyrimidines; D014404:Tubulin; D014635:Valproic Acid; D008094:Lithium; D000068882:Paliperidone Palmitate