Causes of schizophrenia
[10] 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.
[14] 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.
[15] One hypothesis linking delusions in schizophrenia to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D1 and NMDA receptor stimulation.
[20] Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from people with schizophrenia.
[21] 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 schizophrenia.
[22] The large genome-wide association study mentioned above has supported glutamate abnormalities for schizophrenia, reporting several mutations in genes related to glutamatergic neurotransmission, such as GRIN2A, GRIA1, SRR, and GRM3.
[4][5][6] They are local, and one type, the fast-spiking parvalbumin-positive interneuron, has been suggested to play a key role in schizophrenia pathophysiology.
Early studies have identified decreases in GAD67 mRNA and protein in post-mortem brains from those with schizophrenia compared to controls.
Other studies have implicated that a loss-of-function translocation mutation in the DISC1 gene is a major risk factor in developing schizophrenia.
The DISC1 gene codes for a scaffold protein that assists with neurite outgrowth and development of the cortex, operating at several intersections of neurodevelopmental pathways.
[34] It has been suggested that myelination abnormalities could originate from impaired maturation of oligodendrocyte precursor cells,[35] as these have been found to be intact in schizophrenia brains.
Evidence suggests that early stress may contribute to the development of schizophrenia through alterations in the functioning of the immune system.
[37] ACEs and trauma can disrupt the control of immune responses and give rise to lasting inflammatory dysregulation throughout the nervous system.
Abnormal neuronal organization and orientation (dysplasia) has been observed in the entorhinal cortex, hippocampus, and subcortical white matter, although results are not entirely consistent.
[51] It has been hypothesized that in some people, development of schizophrenia is related to intestinal tract dysfunction such as seen with non-celiac gluten sensitivity or abnormalities in the gut microbiota.
Only a fraction of ingested drugs reach the colon, having been already exposed to small intestinal bacteria, and absorbed in the portal circulation.
However, phyla can change in response to many factors including ageing, diet, substance use, and medications – especially antibiotics, laxatives, and antipsychotics.
[55] Beside theories concerning the functional mechanism underlying the disease, structural findings have been identified as well using a wide range of imaging techniques.
[61] Positive symptoms, such as thoughts of being persecuted, were found to be related to the medial prefrontal cortex, amygdala, and hippocampus region.
[63] However, at variance with some findings in individuals with chronic schizophrenia significant group differences of temporal lobe and amygdala volumes are not shown in first-episode people on average.
[70][71] Although quite some variation has been found pertaining to the specific regions affected, the general consensus states a reduced fractional anisotropy in brains from people with schizophrenia versus controls.
During executive function tasks in people with schizophrenia, studies using functional magnetic resonance imaging (fMRI) demonstrated decreased activity relative to controls in the bilateral dorsolateral prefrontal cortex (dlPFC), right anterior cingulate cortex (ACC), and left mediodorsal nucleus of the thalamus.
[72] During emotional processing tasks, reduced activations have been observed in the medial prefrontal cortex, ACC, dlPFC and amygdala.
[74] One meta-analysis of fMRI during acute auditory verbal hallucinations has reported increased activations in areas implicated in language, including the bilateral inferior frontal and post central gyri, as well as the left parietal operculum.
[76] PET scan findings in people with schizophrenia indicate cerebral blood flow decreases in the left parahippocampal region.
PET scans show developmental abnormality in the medial part of the left temporal lobe, and the limbic, and frontal systems.
PET scans carried out during active auditory hallucinations revealed increased blood flow in the thalamus, left hippocampus, right striatum, parahippocampus, orbitofrontal, and cingulate areas.
[79] DOPA PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.
