The olfactory mucosa (OM) is a unique source of regenerative neural tissue that is readily obtainable from living human subjects and thus affords opportunities for the study of psychiatric illnesses. OM tissues can be used, either as ex vivo OM tissue or in vitro OM-derived neural cells, to explore parameters that have been difficult to assess in the brain of living individuals with psychiatric illness. As OM tissues are distinct from brain tissues, an understanding of the neurobiology of the OM is needed to relate findings in these tissues to those of the brain as well as to design and interpret ex vivo or in vitro OM studies. To that end, we discuss the molecular, cellular and functional characteristics of cell types within the olfactory mucosa, describe the organization of the OM and highlight its role in the olfactory neurocircuitry. In addition, we discuss various approaches to in vitro culture of OM-derived cells and their characterization, focusing on the extent to which they reflect the in vivo neurobiology of the OM. Finally, we review studies of ex vivo OM tissues and in vitro OM-derived cells from individuals with psychiatric, neurodegenerative and neurodevelopmental disorders. In particular, we discuss the concordance of this work with postmortem brain studies and highlight possible future approaches, which may offer distinct strengths in comparison to in vitro paradigms based on genomic reprogramming.

The olfactory epithelium constitutes the sole source of regenerating neural cells that can be obtained from a living human. As such, primary cultures derived from olfactory epithelial biopsies can be utilized to study neurobiological characteristics of individuals under different conditions and disease states. Here, using such cultures, we report in vitro generation of cells that exhibit a complex neuronal phenotype, encompassing receptors and signaling pathways pertinent to both olfaction and other aspects of CNS function. Using in situ hybridization, we demonstrate for the first time the native expression of olfactory receptors in cultured cells derived from olfactory epithelial tissue. We further establish the presence and function of olfactory transduction molecules in these cells using immunocytochemistry, calcium imaging and molecular methods. Western blot analysis revealed the expression of neurotransmitter receptors for dopamine (D2R), serotonin (5HT2C) and NMDA subtypes 1 and 2A/2B. Stimulation with dopamine or serotonin enhanced receptor G protein activation in a subtype specific manner, based on 35S-GTP incorporation assay. Functional characteristics of the cultured cells are demonstrated through enhanced tyrosine phosphorylation of NMDAR 2A/2B and recruitment of signaling partners in response to NMDA stimulation. The array of neuronal characteristics observed here establish that proliferating cells derived from the human olfactory epithelium differentiate in vitro to express functional and molecular attributes of mature olfactory neurons. These cultured neural cells exhibit neurotransmitter pathways important in a number of neuropsychiatric disorders. Their ready availability from living humans thus provides a *

Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia: yet molecular underpinnings for such dysregulation are largely unknown. In the postmortem dorsolateral prefrontal cortex, we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2), which is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be due to downregulation of NMDA receptors since MK-801 binding and NMDA receptor complexes in the PSD were in fact increased in schizophrenia cases. At the post-receptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity, which in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms impacting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their impacts on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased RPTPa and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome wide association study results, incorporating 13,394 cases and 34,676 controls, which yielded no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a wider protein-protein interaction based network centered on Src, showed significant enrichment of gene-level associations with schizophrenia compared to other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the post-receptor level and propose Src as a nodal point of convergent dysregulations impacting NMDA receptor pathway via protein-protein associations.

The amygdala brain region has been implicated in the pathophysiology of schizophrenia through emotion processing. However, transcriptome messages in the amygdala of schizophrenia patients have not been well studied. We used RNA sequencing to investigate gene-expression profiling in the amygdala tissues, and identified 569 upregulated and 192 downregulated genes from 22 schizophrenia patients and 24 non-psychiatric controls. Gene functional enrichment analysis demonstrated that the downregulated genes were enriched in pathways such as 'synaptic transmission' and 'behavior', whereas the upregulated genes were significantly over-represented in gene ontology pathways such as 'immune response' and 'blood vessel development'. Co-expression-based gene network analysis identified seven modules including four modules significantly associated with 'synaptic transmission', 'blood vessel development' or 'immune responses'. Taken together, our study provides novel insights into the molecular mechanism of schizophrenia, suggesting that precision-tailored therapeutic approaches aimed at normalizing the expression/function of specific gene networks could be a promising option in schizophrenia.