Side effects of antipsychotics are also linked to the impairment of normal mitochondrial processes functional and ultrastructural mitochondrial malfunctions [ , ]. Recently, Casademont et al. Homocysteine decreases intracellular glutathione peroxidase activity and alters mitochondrial gene expression, structure, and function [ ]. However, mitochondria are key determinants of the excitability and viability of neurons and operate as metabolic and redox hubs. In brief, both useful and harmful side effects of antipsychotics are also linked to the redox-dependent neurotransmitter and redox-dependent neurobiochemical processes.
Burke suggested [ ] that schizophrenic visual hallucinations may be due to deafferentation and dysintegration of definite visual structures that induce an increase in the excitability of deafferented neurons. This deafferentation is associated with an increase in spontaneous activity and synchronization of nerve discharges. Thus, hallucination may be considered as a local paroxysm in some visual structures. Stressful events can lead to redox imbalances and inflammatory processes in the brain.
This atypical redox regulation induces anomalies, including mitochondrial dysfunctions.
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Although gene expression changes are usually attributed to mutations, epigenetic processes also play an essential role in controlling gene expression. Thus, stressful incidents produce metabolic defects that affect epigenetic enzymes and cause uncontrolled overproduction of reactive species that alter DNA methylation and histone modifications. Finally, stressful- driven processes can lead to the regression of synapses and deafferentiation of the brain circuits during neurodevelopment.
This regression entails the loss of synaptic spines, which is under the control of the activity of NMDA receptors on the spines. It is possible that during neurodevelopment in prenatal and early life, genetic and environmental stress factors cause atypical formation of separated local small neuron groups. These partially isolated local neuron groups may work in a random manner as closed-loop synchronized units with increased excitability and produce local paroxysms.
When the adolescent brain is swamped by stress, sex, and growth hormones, and with concomitant increases in the activity of the hypothalamic—pituitary—adrenal system, atypical separated local small neuron groups are also activated. These local neuron groups can remain partially isolated throughout life because they are separated from the perspective of information. This may explain why schizophrenia is such a complex and lifelong brain disorder. However, most intra- and interneuronal signal processes are subject to redox control and modulation in a direct or indirect manner, as was represented in this paper.
It has been accepted that glutamate receptors are the primary molecular structure controlling synaptic plasticity and memory function in the brain. In addition, volume transmission of dopamine can capture free radicals and chelating zinc and other ions in the synaptic cleft and may have an important role in retrograde signaling via metabotropic GluR mechanisms in a G-protein-mediated manner.
Moreover, dopamine can reversibly regulate net inhibitory effect mitochondrial motility. Thus, excess dopamine can produce dysfunctions of mitochondrial distribution i. Because neuronal activity and energy metabolism are direct coupled mechanisms, and regions high in neuronal activity - particularly the glutamatergic ones - have high levels of mitochondrial activity, excess dopamine can perturb neuronal activity via the expression of mitochondrial networks and glutamatergic NMDA receptors.
Additionally, although dopamine o quinone can rapidly recover to dopamine, excess dopamine production - in the context of insufficient antioxidants - results in formation of neurotoxic o semiquinone free radicals from o quinones. These free radicals also cause malfunctions of synaptic processes. In addition, redox-mediated activation of NMDA receptors induces a series of further redox-associated free radical signaling processes, such as NADPH oxidase activity, neuronal nitric oxide synthase nNOS activity, mitochondrial enzyme activity, induction of the arachidonic acid cascade, phospholipase A, and prostaglandin H PGH synthase.
Furthermore, research has shown that serotonin can modulate dopaminergic functions. Since dopamine can exert a net inhibitory effect on mitochondrial movement mitochondria are key determinants of the excitability and viability of neurons and act as metabolic hubs and induce overproduction of H 2 O 2 and superoxides via monoamine oxidase, which inhibits mitochondrial respiration, this restriction of mitochondrial movement fusion, fission, redistribution and respiration can constrain the ongoing neuronal information processes and cause closed-loop synchronized activity in local neuron groups that can produce local paroxysms.
In addition, because the dopamine primordially performs volume transmission and most dopamine receptors are positioned at extrasynaptic sites , excess dopamine production in local deafferented neuron areas can have an especially important regulatory effect on the release of various neurotransmitters and their receptors and on classic synaptic communication.
Because the majority of dopamine monoaminergic varicosities create nonsynaptic contact that enables the release of transmitters directly into the extrasynaptic space, catecholamines and serotonin have free radical scavengers, and the effect of nonsynaptic volume neurotransmission paracrine or diffusion neurotransmission may be not as exact as classical communication by the synaptic mechanism, it is also very important to approach complex causal mechanisms of schizophrenia from a nonsynaptic and redox point of view.
The authors report no conflicts of interest. The authors alone are responsible for the content.
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National Center for Biotechnology Information , U. Journal List Curr Neuropharmacol v. Curr Neuropharmacol. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Here, we show that volume neurotransmission and the redox property of dopamine, as well as redox-regulated processes at glutamate receptors, can contribute significantly to our understanding of schizophrenia. Keywords: Volume neurotransmission, redox regulations, dopamine, glutamate receptors.
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