One of the most common causes of psychosis is schizophrenia, affecting about 1 of the adult population. SchizophreniaÂ is classified asÂ a mental disorderÂ characterized by a breakdown of thought processes and by poor emotional responsiveness. Common symptoms include hallucinationsÂ (most reported areÂ hearing voices),Â delusions, disorganized thinking and speech (APA, 1994; Keltner, Folks, Palmer, & Powers, 1998). It is most commonly diagnosed during late adolescence or early adulthood and an earlier onset, by approximately 4 to 6 years for men than women, exacerbated by stress and responds to dopamine receptor antagonists (Weinberger, 1987).
According to the neurodevelopmental hypothesis, the etiology of schizophrenia may result from a series of pathological processes, including both genetic and environmental factors, which arise during adolescence (1). Therefore downstream effects, which may not be evident for some years could result from earlier influences that disrupted brain development at critical times. These effects include subtle cerebral abnormalities, disrupted neural circuitry and altered neurotransmitter systems. Disruptive influences affecting brain development can be subdivided into the three causative categories: genetic, shared environmental and individual-specific environmental influences (Kendler, Myers, & Neale, 2000; Tsuang, 2000).
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The concept of schizophrenia as a neurodevelopmental disorder is consistent with various epidemiologic and clinical lines of evidence. Earlier neuropathic work has suggested an association between embryonic maldevelopment and schizophrenia (5) and possible neuropathalogical basis for schizophrenia was also suggested by E.salter (6). Evidence for cortical maldevelopment in schizophrenia, through use of animal models, producing behavioural abnormalities or altered sensitivity to dopaminergic drugs in adolescent or adult animals exclusively (7), has reinforced the link between maldevelopment and schizophrenia. According to a 2-hit'' model proposed by Keshavan (8, 9), maldevelopment during 2 critical stages (early brain development and adolescence) can lead to symptoms associated with schizophrenia. Insults during early development may lead to specific neural disruption that would account for the premorbid signs and symptoms observed in individuals diagnosed with schizophrenia at later stages (8). At adolescence, symptoms may result from an excessive loss of synapses and plasticity.
There is evidence to suggest a linkage between neurodevelopmental insults and schizophrenia by presence congenital abnormalities such as agenesis of corpus callosum, stenosis of sylvian aqueduct, cerebral hamartomas, and cavum septum pellucidum (10,11). First trimester abnormalities are associated with the presence of low-set ears, epicanthal eye folds, and wide spaces between the first and second toes (10, 11). There is also evidence supporting abnormalities in patients with schizophrenia consistent with second trimester events (12, 13). The presence of premorbid neurological soft signs, such as slight postering of hands and choreoathetoid movements, has been observed in children during the first 2 years of life who developed schizophrenia in later life. (14, 15, 16, 17). Furthermore, children with a schizophrenic parent and considered high risk have been reported to show higher incidences of, mood and social impairment and poor attention and neuromotor performance. (18, 19). These findings all reveal aspects of abnormal brain devopment during youth as a precursor to schizophrenia in later life and are consistent with the neurodevelopmental hypothesis.
A number of reports indicate that environmental factors, in particular viral infections, can increase the risk for development of schizophrenia (22.23) and epidemiologic research shows an increased incidence of obstetric and perinatal complications, such as periventicular hemorrhages, hypoxia and ischemic injuries in schizophrenic patients (10.20.21). A significant number of births during late winter and spring have been associated with development of schizophrenia has been reported by (24.25), and the influenza virus has been hypothesised as responsible for these cases. Findings in subsequence studies revealed a 5%-15% increase in the number of schizophrenic births during the months of January and March in the northern hemisphere (26.27.28). The excess births have been shown to be independent of methodological artefact and unusual conception patterns in mothers (26.29). The offspring of mothers exposed to the 1957 A2 virus during the second trimester had a 50% increased risk of schizophrenia (25.30). A positive association between prenatal influenza exposure and schizophrenia was shown in a further 9 out of 15 studies, replicating the findings in earlier work (2). These studies showed teratogenicity of the influenza virus on the embryonic brain during the gestation period of 4-7th months (4). The positive association between prenatal influenza exposure and schizophrenia has also been supported by 3 out of 5 cohort and case control studies (31-33).
Other viruses, such as rubella, may also increase the risk of developing schizophrenia following prenatal exposure (34).Further evidence suggests an increased risk of; 10-20 fold following exposure to rubella, 7-fold with influenza exposure during the first trimester and 2.5-fold when maternal antibodies where present against Toxoplasma gondii (35). Nucleotide sequences specific to retroviral polymerase genes have been identified in the cerebrospinal fluid of 28.6% of subjects with acute onset schizophrenia and 5% of subjects with chronic schizophrenia. No such sequences where identified in the normal subject groups or groups with non-inflammatory neurological illnesses. (22.23). However, variations in the handling and storage time of samples and other regional differences were reported (23). A more recent study was conducted in 2008 examining the human endogenous retrovirus type "W" (HERV-W) GAG and envelope protein antigenemia in the serum of schizophrenic patients using an immunoassay (220). Results showed a positive antigenemia for, ENV and GAG was found in 23 of 49 (47%) and 24 of 49 (49%) of schizophrenic patients respectively (219). In comparison, only 1 of 30 (3%) for ENV and 2 of 49 (4%) for GAG were positive control subjects (p <.01 for ENV; p < .001 for GAG), further emphasizing the link between schizophrenia and retroviruses (219). In line with these studies and previous epidemiological reports, the general consensus of schizophrenia suggests its development may arise from the presence of a shared phenotype, consisting of a group of disorders which involve a combination of genetic influences and environmental risks that affect the brain maturational processes (22). Early identification of potential environmental risk factors, such as the endogenous retrovirus type W, would allow for specific targeting and repression of these genes (23). Implementation of vaccination against viruses, such as influenza in high risk individuals would be an alternative approach towards influencing schizophrenia development (22).
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Mechanisms that have been suggested for the viral transmission from mother to foetus include 2 pathways. Firstly, by direct viral infection, evidence presented from clinical and experimental reports show (36-39) possible viral loading to the foetus via trans-placental passage of influenza A-type from infected mothers. Research conducted using mouse models, in which 14 day pregnant C57BL/6 mice were intranasally instillated with neuroadapted influenza A/WSN/33 strain, showed that viral RNA and nucleoprotein were detected in the foetal brains of exposed offspring. Furthermore, results revealed the persistence of viral RNA in brains of affected offspring for at least 90 days during postnatal life, thus providing evidence for the transplacental passage of influenza virus and persistence of viral components in the brains of these animals into young adulthood (38). Additionally, the presence of viral RNA, encoding for the non-structural NS1 protein involved in regulation of host cell metabolism (40), was discovered in the midbrain of TAP1 mutant mice injected 10-17 months prior with the influenza A virus (38). Various in vitro studies show the ability of influenza A to selectively target multiple cells located in the brain, including schwann cells (41), astrocytes, microglial cells and neurons (36) and hippocampal GABAergic cells (42.43)