components CSPGs and HAPLNs and psychiatric conditions including schizophrenia3). Ji et al. performed transcription-neuroimaging association analysis to find genes associated with gray matter volume (GMV) alterations in SCZ4). HAPLN4 showed the largest negative correlation: the expression of this gene was lower in the brain regions with more GMV reduction in patients with SCZ. The authors suggested that the low expression level of HAPLN4 might lead to GMV reduction by influencing the ECM and PNNs. This result is in line with our previous findings that HAPLN4 deficiency in mice led to a decrease in the extracellular space volume fraction but only in the aged brain5,6). Recent integrative, genetic, epigenetic and expression data analysis identified eight psychiatric disease risk genes including HAPLN47). In addition, prepulse inhibition, an endophenotype of schizophrenia, was reduced in Hapln4-KO mice8). HAPLN4 is expressed in PNNs, mainly in the brainstem and cerebellum. PNNs are typically found around fast-spiking GABAergic interneurons expressing parvalbumin but interestingly also exist surrounding other neurons, such as the neurons in the deep cerebellar nuclei (DCN) and medial nucleus of the trapezoid body (MNTB), which are the postsynaptic neurons of large axo-somatic synapses adapted for fast signaling. To assess the functional role of HAPLN4 in the formation and maintenance of synapses, we have introduced combined electrophysiological and morphological assessment in the Hapln4-KO. We could take advantage of the accessibility of these synapses to patch-clamp recordings in brain slices from HAPLN4 deficient mice. In DCN neurons of Hapln4-KO mice, inhibitory synaptic strengths were reduced as compared to those in wild-type mice, whereas the properties of excitatory synapses were unaffected. The reduced induced post-synaptic current amplitudes were mainly because of reduced numbers of releasable vesicles. Moreover, HAPLN4 deficiency reduced the number of Purkinje cell GABAergic terminals in the DCN. These results demonstrate that HAPLN4 is a PNN component that selectively contributes to formation and transmission of PC-DCN synapses The etiology of schizophrenia (SCZ) is based on the neurodevelopmental disorder hypothesis, which proposes that multiple genetic and early environmental factors impair neurodevelopment during the fetal period and early postnatal period, resulting in the formation of fragile neural circuits, which are then subjected to psychosocial stresses during puberty and later in life. Since many postmortem brain studies of SCZ have reported abnormal GABAergic transmission in cortical parvalbumin-positive interneurons (PVI) of SCZ patients, PVI neurons are expected to be one of the neurons involved in the pathogenesis of SCZ.Perineuronal nets (PNNs) are pericellular coats of condensed matrix that enwrap the cell bodies and dendrites of certain neurons in the adult central nervous system. PNNs primarily consist of hyaluronan, chondroitin sulfate proteoglycans (CSPGs) of the lectican family, tenascin-R, and link proteins (HAPLNs) as a core extracellular matrix (ECM)1). PNNs are prominently formed in PVI neurons through poverty. Recent postmortem brain studies of schizophrenia patients suggest that the loss of PNN in the prefrontal cortex correlates with patients' cognitive dysfunction. In addition, numerous reports of abnormalities in GABAergic transmission in the cortical PVI of schizophrenic patients suggest that PNN is protective against oxidative stress. A current hypothesis is that loss of the neuroprotective activity of PNNs renders the fast-spiking PV+ oxidant-generating neurons vulnerable to oxidative stress1).We hypothesized that abnormalities in PNNs with complex functions, resulting in altered vulnerability and plasticity of PV neurons, may increase the risk of developing schizophrenia. Although aberrations in PNN of PVI neurons are implicated in SCZ, it remains unclear how the distribution and formation of PNNs progressively change during development and how these changes affect normal behavior and physiology. To gain insights into the PNN development during puberty, we focused on the HAPLN molecule as an organizer for PNN formation2). In this study we focused on HAPLN4 for the following reason. A genetic association transcriptomics study has found associations between changes in the expression of the PNN 71Potential impact of perineuronal net on the pathogenesis of SchizophreniaToshitaka OohashiDepartment of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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