Choroid plexus and mis-regulation of brain OTX2 in schizophrenia

During critical periods of postnatal brain development, maturation of inhibitory neuronal circuits and formation of surrounding perineuronal nets (PNNs) result in a transition from juvenile, highly malleable, forms of plasticity to adult restricted modalities. Emerging evidence from the visual cortex points to a key role for the orthodenticle homeobox 2 (OTX2) protein in such critical developmental transitions. OTX2 internalization in neurons ensheated by PNNs induces their maturation and is necessary to open, then close, critical periods of plasticity. PNN degradation reinstates juvenile forms of plasticity in adult. Converging evidence suggests that OTX2/PNN interactions may affect brain regions beyond the visual cortex, including the amygdala and prefrontal cortex (PFC). Notably, OTX2 is not produced within the adult brain, raising the question as to its origin. Results from rodents point to the choroid plexus (CP) as a global source, implying that altered OTX2 synthesis outside the brain parenchyma may have a profound impact on key neuronal functions. Our preliminary data shows that in humans, OTX2 is detectable in the cerebrospinal fluid (CFS) and markedly decreased in subjects with schizophrenia (SZ), as in the amygdala and PFC. We propose a complementary, truly translational approach, combining human studies on postmortem amygdala, PFC and CSF and CP epithelial cell cultures, with animal model approaches including conditional gene-targeting in mice, EEG and optogenetic assays of neural-network function (oscillations), and whole-cell electrophysiology. These investigations will test the hypothesis that OTX2 originating from the CP is pivotal to neuronal maturation and circuit plasticity in the PFC and amygdala, brain regions involved in cognitive and emotion processing, and in the pathophysiology of SZ. In SZ, we hypothesize that OTX2 deficits occur in the CP and CSF as well as in the amygdala and PFC in association with PNN loss and neuronal immaturity. The potential for systemic modulation of these mechanisms through the CP, tested in these studies, may broaden our understanding of brain plasticity and open novel therapeutic approaches to SZ.