Schizophrenia is a neurodevelopmental disorder reflecting a convergence of genetic risk and early life stress. The slow progression to first psychotic episode represents both a window of vulnerability as well as opportunity for therapeutic intervention. Here, we consider recent neurobiological insight into the cellular and molecular components of developmental critical periods and their vulnerability to redox dysregulation. In particular, the consistent loss of parvalbumin-positive interneuron (PVI) function and their surrounding perineuronal nets (PNNs) as well as myelination in patient brains is consistent with a delayed or extended period of circuit instability. This linkage to critical period triggers (PVI) and brakes (PNN, myelin) implicates mistimed trajectories of brain development in mental illness. Strategically introduced antioxidant treatment or later reinforcement of molecular brakes may then offer a novel prophylactic psychiatry.
A mention of circadian clock genes is made:
“One interesting example of relevance to SZ is the role of Clock genes in the neocortex. Circadian rhythms have been shown to regulate redox homeostasis in the brain, and disruption of circadian genes causes neuronal oxidative damage. Aberrant circadian rhythmicity has long been linked to mental illness, and very recent work identifies a postnatal emergence of rhythmic gene expression outside the suprachiasmatic nucleus. Maturation of PVI is particularly sensitive to Clock/Bmal gene deletion with the consequence of protracted CP timing into adulthood. Cell-specific transcriptome profiling of PVI by FACS reveals altered expression of genes downstream of CLOCK related to the respiratory chain (eg, Cox and Nduf family genes) and redox regulation (eg, Gpx4). Thus, circadian clock genes may preserve PVI integrity and prevent the manic behaviors observed when they are disrupted.”
For a moment, I’ll expand on some other findings related to circadian rhythms:
Dopamine acts through cryptochrome to promote acute arousal . A mutation in CLOCK leads to altered dopamine receptor function  and circadian clock-deficient cryptochrome knockout mice demonstrate cognitive dysfunction, elevated anxiety, and reduced cocaine response .
“… loss of CLOCK function increases dopamine release and turnover in striatum as indicated by increased levels of metabolites HVA and DOPAC, and enhances sensitivity to dopamine receptor antagonists. Interestingly, this enlarged dopaminergic tone results in downstream changes in dopamine receptor (DR) levels with a surprising augmentation of both D1- and D2-type DR protein, but a significant shift in the ratio of D1:D2 receptors in favor of D2 receptor signaling. These effects have functional consequences for both behavior and intracellular signaling, with alterations in locomotor responses to both D1-type and D2-type specific agonists and a blunted response to cAMP activation in the ClockΔ19 mutants. Taken together, these studies further elucidate the abnormalities in dopaminergic transmission that underlie mood, activity, and addictive behaviors.”
Epigenetic modifications induced by circadian rhythmicity have been investigated, including in the formation of memories 
More broadly, it is hypothesised that the cryptochrome compass system mediates stress responses across the hypothalamic-pituitary-adrenal (HPA) axis (including alterations to circadian behaviour) and may play a role in responses to changes in the geomagnetic field 
Circadian clock proteins in mood regulation.
Links between Circadian Rhythms and Psychiatric Disease.
A highly tunable dopaminergic oscillator generates ultradian rhythms of behavioral arousal
Back to the original article…
Three broad areas are covered:
1.Excitatory-inhibitory (E-I) circuit balance is a trigger.
2. Synaptic pruning and homeostasis mediate plasticity.
3. Molecular “brakes” limit adult plasticity to stabilize neural networks initially sculpted by experience.
…oxidative stress or redox dysregulation contribute crucially to PVI and myelin impairment in SZ. Moreover, as reviewed in Steullet et al, dysregulation of redox homeostasis is fully reciprocal to neuroinflammation and NMDA-R hypofunction (figure 2). This triad constitutes one central pathophysiological “hub” upon which various genetic and environmental risk factors converge during neurodevelopment, leading to structural and functional connectivity impairments. Drugs targeting the triadic hub of oxidative stress, neuroinflammation, or NMDA-R hypofunction would be promising candidates to prevent deleterious effects on cortical and hippocampal PVI and oligodendrocytes/myelin. As such treatments (eg, omega-3, sulforaphane, NAC) should be applied in early phases of the illness, they should be devoid of serious side-effects. Adolescent treatment with atypical antipsychotics (risperidone, clozapine) in the prenatal immune activation model can also prevent hippocampal volume loss and lateral ventricle enlargement as well as behavioral abnormalities. However, whether this is mediated through PVI/myelin and CP plasticity is unknown and their serious side effects would temper their use from a preventive perspective.”
“Converging evidence also points to membrane phospholipid and polyunsaturated fatty acid (PUFA) defects in early course and chronic SZ. …As membrane PUFAs are highly susceptible to free radical insults, increased oxidative stress may be one of the mechanisms responsible for membrane PUFA reduction. Indeed, oxidative stress in first-episode SZ is associated with decreased PUFA content and increased breakdown products of membrane lipids, possibly with a familial basis. In particular, decreased membrane PUFA levels are associated with increased levels of total lipid peroxides, decreased levels of vitamin E, and increased severity of negative symptoms. The use of PUFA, particularly omega-3, is a potential alternative and adjunct to current antipsychotics treatments. Omega-3 fatty acids are effective in reducing oxidative stress in preclinical models and dietary supplementation may be beneficial in psychiatric conditions. Omega-3 might be most promising in preventing the transition to psychosis for at-risk mental state subjects.”
“Sulforaphane is a dietary isothiocyanate found in broccoli sprouts and has gained attention as a natural, and safe, anticancer compound. Evidence suggests that sulforaphane is able to reduce oxidative stress by activating the Nrf-2 antioxidant response element pathway, upregulating phase II detoxification enzymes and antioxidant proteins. Sulforaphane was shown to protect against antipsychotic-induced oxidative stress in dopaminergic neuroblastoma cells by increasing GSH and quinone oxidoreductase (NQO1) activity. In mice injected with phencyclidine, sulforaphane attenuated prepulse inhibition (PPI) deficits in a dose-dependent manner, as well as reducing hyperlocomotion at higher doses.”
“NAC, known as a GSH precursor, also has antioxidant and anti-inflammatory properties per se and can regulate glutamatergic neurotransmission. It represents a safe and potential compound for the prevention or treatment of SZ and other psychiatric disorders. NAC is deacetylated to form cysteine, the rate-limiting precursor of GSH, and therefore yields upregulation of GSH synthesis when cells face an excess of ROS production. NAC also participates to the control of the intracellular redox state by supplying cysteine into the cystine/cysteine redox couple.
In Gclm-KO mice, NAC prevents PVI and PNN deficits induced by an oxidative insult during postnatal development and normalizes most of the neurochemical profiles, including the glutamine/glutamate ratio known to be altered in a similar way in first-episode SZ patients.Likewise, NAC reduces oxidative stress, protects prefrontal PVI, and prevents deficits in MMN and PPI in the developing rat neonatal ventral hippocampal lesion model which is independent of redox manipulation and shows E-I imbalance.
NAC also prevents myelin impairment following a maternal immune challenge, reestablishes normal function of the cystine/glutamate antiporter and GSH levels in MAM-injected rats, normalizes extracellular glutamate levels, and attenuates behavioral anomalies in phencyclidine-treated rats. It reduces oxidative stress, rescues abnormal behavioral phenotype in G72/G30 transgenic mice, and reverses the social isolation-induced changes in corticostriatal monoamine levels. Thus, NAC has beneficial effects across a very diverse panel of animal models relevant to SZ.
In a first randomized double-blind placebo-controlled trial, an add-on treatment of NAC in chronic patients diminished negative symptoms and improved global functioning. Two additional studies also demonstrate that chronic patients improved with supplemental NAC, particularly in their negative symptoms. Moreover, NAC normalized neuronal activity and connectivity and improved MMN, an auditory-related, NMDA-dependent evoked potential typically impaired in SZ. Although not performed during development, these studies can be considered as a proof-of-concept, pointing to the efficacy of an antioxidant and possibly favoring the closure of a pathological CP.
NAC also increased phase synchronization of neuronal activity over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. However, the beneficial effect of NAC has to be taken with caution because the current data are based on only a few studies showing relatively moderate clinical improvement in chronic SZ patients, probably due to the low bioavailability and membrane permeability of NAC which enters the brain at a very modest rate. The development of other molecules with better bioavailability and blood-brain barrier permeability is therefore needed.”
“…Du and Grace have reported that peripubertal administration of diazepam prevents the increase in dopamine neuron activity and blunts the behavioural hyper-responsivity to amphetamine in the developmental MAM rats. This effect of diazepam may be mediated by normalizing PVI/CP plasticity because CP delay in the GAD65 deletion model can be rescued by enhancing GABA transmission directly with diazepam.”
“Because the disruption of PVI maturation and myelination would combine to delay or prolong CP plasticity, it may also be useful to strategically introduce well-timed brakes on plasticity or to lift them as needed (as in amblyopia recovery). Several candidate factors have recently been identified, including PNN-promoting transcription factors (Otx2), modulators of cholinergic transmission (Lynx1), or epigenetic regulators (HDAC). An intriguing target may be the NgR/PirB signalling complex which interacts with both chondroitin sulfate proteoglycans in the PNN as well as myelin molecules. Notably, the plasticity modulating effect of NgR deletion has recently been traced to PVI circuits specifically. Further methods to modulate PVI maturational state, ideally from the blood periphery are desirable as therapeutic agents. The peculiar localization of noncell autonomous factors, such as Otx2 synthesis within the accessible choroid plexus, particularly appealing”