The exact pathophysiology of<unk>  remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis. Other theories include the specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress. Dopamine dysfunction The first formulations of the dopamine hypothesis of<unk>  came from post-mortem studies finding increased numbers of D2/D3 receptors in the striatum, and elevated cerebrospinal fluid levels of dopamine metabolites. Subsequently, most antipsychotics were found to have affinity for D2 receptors. Later investigations have suggested a link between striatal dopamine synthesis and positive symptoms, as well as increased dopamine transmission in subcortical regions, and decreased transmission in cortical regions. A meta-analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of dopamine transporters or dopamine D2/D3 receptors. Both studies using radio labeled L-DOPA, an indicator of dopamine synthesis, and studies using amphetamine release challenges observed significant differences between those with<unk>  and control. These findings were interpreted as increased synthesis of dopamine, and increased release of dopamine respectively. These findings were localized to the striatum, and were noted to be limited by the quality of studies used. A large degree of inconsistency has been observed in D2/D3 receptor binding, although a small but nonsignificant reduction in thalamic availability has been found. The inconsistent findings with respect to receptor expression has been emphasized as not precluding dysfunction in dopamine receptors, as many factors such as regional heterogeneity and medication status may lead to variable findings. When combined with findings in presynaptic dopamine function, most evidence suggests dysregulation of dopamine in<unk> . Exactly how dopamine dysregulation can contribute to<unk>  symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations, while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions. Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex. One hypothesis linking delusions in<unk>  to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D1 and NMDA receptor stimulation. This, when combined with hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs. Glutamate dysfunction Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of<unk> . This has largely been suggested by lower levels of glutamate receptors found in postmortem brains of people previously diagnosed with<unk>  and the discovery that glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition. The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in<unk> , have suggested an important mediating (and possibly causal) role of glutamate pathways in<unk> . Positive symptoms fail however to respond to glutamatergic medication. Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from people with<unk> . In particular, the expression of mRNA for the NR1 receptor subunit, as well as the protein itself is reduced in the prefrontal cortex in post-mortem studies of those with<unk> . Fewer studies have examined other subunits, and results have been equivocal, except for a reduction in prefrontal NRC2. The large genome-wide association study mentioned above has supported glutamate abnormalities for<unk> , reporting several mutations in genes related to glutamatergic neurotransmission, such as GRIN2A, GRIA1, SRR, and GRM3. Interneuron dysfunction Another hypothesis is closely related to the glutamate hypothesis, and involves the dysfunction of inhibitory GABAergic interneurons in the brain. They are local, and one type, the fast-spiking parvalbumin-positive interneuron, has been suggested to play a key role in<unk>  pathophysiology. Early studies have identified decreases in GAD67 mRNA and protein in post-mortem brains from those with<unk>  compared to controls. These reductions were found in only a subset of cortical interneurons. Furthermore, GAD67 mRNA was completely undetectable in a subset of interneurons also expressing parvalbumin. Levels of parvalbumin protein and mRNA were also found to be lower in various regions in the brain. Actual numbers of parvalbumin interneurons have been found to be unchanged in these studies, however, except for a single study showing a decrease in parvalbumin interneurons in the hippocampus. Finally, excitatory synapse density is lower selectively on parvalbumin interneurons in<unk>  and predicts the activity-dependent down-regulation of parvalbumin and GAD67. Together, this suggests that parvalbumin interneurons are somehow specifically affected in the disease. Several studies have tried to assess levels in GABA in vivo in those with<unk> , but these findings have remained inconclusive. EEG studies have indirectly also pointed to interneuron dysfunction in<unk>  (see below). These studies have pointed to abnormalities in oscillatory activity in<unk> , particularly in the gamma band (30–80 Hz). Gamma band activity appears to originate from intact functioning parvalbumin-positive interneuron. Together with the post-mortem findings, these EEG abnormalities point to a role for dysfunctional parvalbumin interneurons in<unk> . The largest meta-analysis on copy-number variations (CNVs), structural abnormalities in the form of genetic deletions or duplications, to date for<unk> , published in 2015, was the first genetic evidence for the broad involvement of GABAergic neurotransmission. Myelination abnormalities Another hypothesis states that abnormalities in myelination are a core pathophysiology of<unk> . This theory originated from structural imaging studies, which found that white matter regions, in addition to grey matter regions, showed volumetric reductions in people with<unk> . In addition, gene expression studies have shown abnormalities in myelination and oligodendrocytes in the post-mortem brains. Furthermore, oligodendrocyte numbers appear to be reduced in several post-mortem studies. It has been suggested that myelination abnormalities could originate from impaired maturation of oligodendrocyte precursor cells, as these have been found to be intact in<unk>  brains. Immune system abnormalities Inflammation and immune system abnormalities are seen to be key<unk>  for the development of<unk> . A number of causes and consequences of inflammation have been implicated many of which are stress-related. Evidence suggests that early stress may contribute to the development of<unk>  through alterations in the functioning of the immune system. Adverse childhood experiences (ACEs) for example can give toxic stress. ACEs and trauma can disrupt the control of immune responses and give rise to lasting inflammatory dysregulation throughout the nervous system. Chronic trauma can promote chronic immune system activation. Persistent systemic inflammation may lead to damage of the peripheral tissue and a subsequent breach of the blood-brain-barrier. If this happens microglia can be activated and cause neuroinflammation. Inflammation can result in oxidative stress in<unk>  which has damaging consequences for brain cells. The immune hypothesis is supported by findings of high levels of immune markers in the blood of people with<unk> . High levels of immune markers have also been associated with having more severe psychotic symptoms. Furthermore, a meta-analysis of genome-wide association studies discovered that 129 out of 136 single-nucleotide polymorphisms significantly associated with<unk>  were located in the major histocompatibility complex region of the genome. A systematic review investigating neuroinflammatory markers in post-mortem<unk>  brains has shown quite some variability, with some studies showing alterations in various markers but others failing to find any differences. Oxidative stress Another theory that has gained support is that a large role is played in the disease by oxidative stress. Redox dysregulation in early development can potentially influence development of different cell types that have been shown to be impaired in the disease. Oxidative stress has also been indicated through genetic studies into<unk> . Oxidative stress has been shown to affect maturation of oligodendrocytes, the myelinating cell types in the brain, potentially underlying the white matter abnormalities found in the brain (see below). Furthermore, oxidative stress could also influence the development of GABAergic interneurons, which have also been found to be dysregulated in<unk>  (see above). Evidence that oxidative stress and oxidative DNA damage are increased in various tissues of people with<unk>  has been reviewed by Markkanen et al. The presence of increased oxidative DNA damage may be due, in part, to insufficient repair of such damages. Several studies have linked polymorphisms in DNA repair genes to the development of<unk> . In particular, the base excision repair protein XRCC1 has been implicated. Neuropathology The most consistent finding in post-mortem examinations of brain tissue is a lack of neurodegenerative lesions or gliosis. Abnormal neuronal organization and orientation (dysplasia) has been observed in the entorhinal cortex, hippocampus, and subcortical white matter, although results are not entirely consistent. A more consistent cytoarchitectural finding is reduced volume of purkinje cells and pyramidal cells in the hippocampus. This is consistent with the observation of decreased presynaptic terminals in the hippocampus, and a reduction in dendritic spines in the prefrontal cortex. The reductions in prefrontal and increase in striatal spine densities seem to be
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