Do genes and environment meet to regulate cerebrospinal fluid dynamics? Relevance for schizophrenia

Abstract

Schizophrenia is a neurodevelopment disorder in which the interplay of genes and environment contributes to disease onset and establishment. The most consistent pathological feature in schizophrenic patients is an enlargement of the brain ventricles. Yet, so far, no study has related this finding with dysfunction of the choroid plexus (CP), the epithelial cell monolayer located within the brain ventricles that is responsible for the production of most of the cerebrospinal fluid (CSF). Enlarged brain ventricles are already present at the time of disease onset (young adulthood) and, of notice, isolated mild ventriculomegaly detected in utero is associated with subsequent mild neurodevelopmental abnormalities similar to those observed in children at high risk of developing schizophrenia. Here we propose that altered CP/CSF dynamics during neurodevelopment may be considered a risk, causative and/or participating factor for development of schizophrenia.

Therapeutic implications of the choroid plexus–cerebrospinal fluid interface in neuropsychiatric disorders

“…The most consistent pathological feature of schizophrenia is enlargement of the brain ventricles, which is present at the time of disease onset (Palha et al, 2012;Steen et al, 2006). This enlargement could be linked to dysfunction of CSF secretion at the CP because AQP1 and AQP4 are abundantly expressed at the CP, and AQP1 is located within the genetic loci that are strongly implicated in schizophrenia (Palha et al, 2012;Brown et al, 2004). Furthermore, it has been shown that the incidence of CP calcifications (CPC) before the age of 25 years is relatively high in schizophrenic patients (40%) compared to controls (20%) (Bersani et al, 1999).…”

“…Not every schizophrenic individual responds to therapy and since drugs improving negative symptoms are lacking, there is a need for new therapeutic, and maybe preventive, approaches (Arroll et al, 2014). The most consistent pathological feature of schizophrenia is enlargement of the brain ventricles, which is present at the time of disease onset (Palha et al, 2012;Steen et al, 2006). This enlargement could be linked to dysfunction of CSF secretion at the CP because AQP1 and AQP4 are abundantly expressed at the CP, and AQP1 is located within the genetic loci that are strongly implicated in schizophrenia (Palha et al, 2012;Brown et al, 2004).…”

“…Moreover, CPC size appears to be specifically associated with hallucinations but not with other positive symptoms (Sandyk, 1993). Consequently, altered CP/CSF dynamics during neurodevelopment might be a risk, causative and/or participating factor for development of schizophrenia (Palha et al, 2012).…”

“…Changes at the CP-CSF interface during neurodevelopment are considered risk, causative and/or participating factors for the development of neuropsychiatric disorders (Palha et al, 2012). These alterations include for example the disturbed production of neurogenesis-related molecules by the CP, such as retinoic acid (Yamamoto et al, 1996(Yamamoto et al, , 1998, insulin growth factor II (IGF II) (Lehtinen and Walsh, 2011) and Slit1 (Sawamoto et al, 2006), or inflammatory -induced proteins that modulate neurogenesis, such as Slit2 (Marques et al, 2009), and disturbances in CSF formation, circulation and/or homeostasis (Palha et al, 2012). Therefore, this gives a window of opportunity for therapeutic targeting of neural maturation and brain plasticity in the early years of life, in people at risk, to prevent the exacerbation of social, emotional and cognitive deficits into a full-blown neuropsychiatric disorder (Misra, 2014).…”

Serum Prolidase Activity as a Biomarker for Choroid Plexus Calcification

“…CP is highly vulnerable to damage on head injuries, infections, and ischemic conditions (Maxwell et al 1992). Furthermore, Palha et al (2012) mentioned acute peripheral inflammation in CP.…”