New Model of Action for Mood Stabilizers: Phosphoproteome from Rat Pre-Frontal Cortex Synaptoneurosomal Preparations

Abstract

BackgroundMitochondrial 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.HypothesisMitochondrial 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.MethodsSynaptoneurosomal 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.ResultsLithium, 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.ConclusionsMood 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.

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

“…Typical APDs are more potent inhibitors compared to atypical APDs [43]. Haloperidol and clozapine tend to inhibit anterograde transport of mitochondria stranding them in perinuclear locations [44,45]. This sequestration of mitochondria away from axon and spines could reduce the amount of energy released by mitochondria, which directly affects neurotransmission and adequate calcium buffering in synapses.…”

Purinergic Signaling and Energy Homeostasis in Psychiatric Disorders

“…It is becoming increasingly clear that the apparent overlap in efficacy of mood stabilizers and antipsychotic drugs for the treatment of SZ symptoms is likely due to a common mechanism acting to correct malfunctioning mitochondria, whose dysfunction causes the aberrant release of ATP and an increased release of inflammatory mediators [176,177]. For example, the atypical antipsychotic paliperidone, as well as the mood stabilizers lithium and valproic acid induce increases in expression of synaptic and mitochondrial proteins, promoting mitochondrial migration to the synapse [178,179]. In line with this, administration of the glutamate receptor antagonist ketamine, has recently been shown to specifically affect mitochondrial respiratory chain complexes [180].…”

Can a systems approach produce a better understanding of mood disorders?

“…There have been many studies to examine the transcriptome impact of affective disorder treatments, most commonly lithium and valproate [84][85][86]. In addition, an increasing number of studies are looking at other levels of global organisation, such as the epigenome [87,88], proteome [89,90], phosphoproteome [91], and the metabolome [92]. It should be noted that for these therapeutic agents, their exact mode of action is unclear, and the high doses required to achieve efficacy suggest a non-specific, multi-target effect.…”