25.4 PROMOTING MYELIN REPAIR RESCUES MICE FROM SCHIZOPHRENIA-LIKE BEHAVIOR INDUCED BY SOCIAL ISOLATION

Abstract Background Although pathological and genetic evidence suggest that oligodendrocyte (OL) or myelin deficits are associated with schizophrenia, the contribution of OL/myelin deficits to its etiology has not been clearly dissected, because OL/myelin abnormalities may be a concomitant phenomenon during the pathogenesis of schizophrenia. Methods Using olig2 ablation specifically in OLs (olig2 CKO) mice, we detected myelin development status and animal behaviors under normal condition or subjected to social isolation. We also examined the therapeutic effect of FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) on animal behaviors. Results Our results demonstrated that deleting of olig2 leaded to impaired development of OLs and myelin deficit from postnatal day14 (P14) to P56, preferentially in cerebral cortex, and these young adult Olig2 KO mice showed anxiety-like behavior, motor skill learning deficit and cognitive deficit. Moreover, Olig2 CKO mice exhibited earlier social avoidance behavior than the WT littermates under prolonged social isolation, indicating that myelin deficit may enhance risk of schizophrenia upon environmental stress attacking. Interestingly, enhancing oligodendrocyte generation and myelin repair by quetiapine or clemastine successfully reversed the above phenotype. Discussion Taking together, promoting myelin repair may present a new therapeutic strategy against schizophrenia.

were submitted to state-of-the art large-scale proteomic analyses.In silico systems biology was employed to identify key pathways in the studied processes.Results: MK-801-treated astrocytes, and especially MK-801-treated oligodendrocytes displayed several proteins differentially expressed which overlapped with previous findings of schizophrenia human brains.On the other hand, MK801-treated neurons displayed very few differences in their proteome, an overlap with previous findings in human brain tissue below 10%.More interestingly, the dysregulation of glycolytic enzymes in MK801treated oligodendrocytes are very similar to our observations in schizophrenia brain tissue, corroborating with recent findings about of the importance of oligodendrocytes in the energy status of the brain.In oligodendrocytes, antipsychotics displayed differences in translational machinery and eIF2 signaling.Findings on cerebral organoids also showed overlaps with previous postmortem data, mainly on synaptic proteins and specially energy metabolism-associated pathways.
Discussion: These findings hold potential for the investigation of developmental and evolutionary features of schizophrenia brains and provides targets to be drug-screened as well as leads to the schizophrenia pathobiology.

PROMOTING MYELIN REPAIR RESCUES MICE FROM SCHIZOPHRENIA-LIKE BEHAVIOR INDUCED BY SOCIAL ISOLATION
Lan Xiao* ,1 1 Third Military Medical University Background: Although pathological and genetic evidence suggest that oligodendrocyte (OL) or myelin deficits are associated with schizophrenia, the contribution of OL/myelin deficits to its etiology has not been clearly dissected, because OL/myelin abnormalities may be a concomitant phenomenon during the pathogenesis of schizophrenia.Methods: Using olig2 ablation specifically in OLs (olig2 CKO) mice, we detected myelin development status and animal behaviors under normal condition or subjected to social isolation.We also examined the therapeutic effect of FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) on animal behaviors.Results: Our results demonstrated that deleting of olig2 leaded to impaired development of OLs and myelin deficit from postnatal day14 (P14) to P56, preferentially in cerebral cortex, and these young adult Olig2 KO mice showed anxiety-like behavior, motor skill learning deficit and cognitive deficit.Moreover, Olig2 CKO mice exhibited earlier social avoidance behavior than the WT littermates under prolonged social isolation, indicating that myelin deficit may enhance risk of schizophrenia upon environmental stress attacking.Interestingly, enhancing oligodendrocyte generation and myelin repair by quetiapine or clemastine successfully reversed the above phenotype.Discussion: Taking together, promoting myelin repair may present a new therapeutic strategy against schizophrenia.

NOVEL APPROACHES TO PSYCHOSIS RISK: MOVEMENT, STRESS MODULATION, REWARD AND LANGUAGE Cheryl Corcoran Icahn School of Medicine at Mount Sinai
Overall Abstract: Research on psychosis risk now encompasses novel and innovative approaches for understanding not only positive symptoms, but also impairment in sensorimotor function, stress regulation, reward learning, and language.These include the use of machine learning and cluster analysis with resting state functional connectivity analyses, in vivo measures of dopamine function in response to stress, computational modeling, and automated natural language processing analyses in collaboration with IBM.First, Vijay Mittal will describe subtypes of clinical risk, identifying a group with aggregated measures of sensorimotor dysfunction, developmental markers, negative symptoms and cognitive deficits, who have a discrete pattern of corticostriatal connectivity.Second, Romina Mizrahi will present her results from a study of dopamine response to stress in prefrontal cortex, using positron emission tomography, and correlations with cortisol release, across stages of illness, including schizophrenia and clinical risk, with healthy volunteers for comparison.Third, James Waltz will present data on the computational processes that may underlie both positive and negative symptoms, in respect to dopaminebased signals of salience.These include aberrant or erratic salience signaling, as well as a decreased ability to identify relevant salient stimuli, which could impair reward learning and motivation.His cohort includes individuals with psychosis, and those at clinical risk for it, as well as non-psychosis patient controls.Fourth, Cheryl Corcoran will describe the use of automated natural language processing (NLP), with machine learning (ML) to identify semantic and syntactic features that predict psychosis onset.She will show data on cross-validation of the classifier in a second risk cohort, and its correlation with demographics and manual linguistic features.Overall, there is an apparent norm of semantic coherence and syntactic complexity from which individuals with psychosis deviate, even prior to its onset.Finally, the discussant will review these data in the context of his experience and ongoing leadership in the field of psychosis risk research, leading audience discussion, and outlining a roadmap for future research in the field.

MOTOR SUBTYPES AND PREDICTION OF COURSE IN PSYCHOSIS RISK YOUTH
Vijay Mittal* ,1 , Derek Dean 2 , Sebastian Walther 3 , Tina Gupta 1 , Teresa Vargas 1 , Juston Osborn 1 1 Northwestern University; 2 University of Colorado Boulder; 3 University Hospital of Psychiatry Background: Prominent etiological conceptions of psychosis implicate abnormal cortico-striatal circuits.Dysfunction in these critical systems, responsible for filtering information and modulating higher-order function, may account for heterogeneous presentations of symptoms and characteristics of psychosis.Collectively, a body of work from our group and from other teams indicates that evaluating select motor behaviors and abnormalities, which directly reflect function of these circuits, may be a useful method for understanding and predicting the neural underpinnings of psychosis.In the context of the psychosis risk period, partitioning clinical high-risk (CHR) youth based on objective behavior may help guide early detection and intervention efforts, and provide a novel perspective on different etiological pathways or patient subtypes.Methods: Using an unsupervised machine learning approach, 69 CHR young adults were included in a K-means cluster analysis based on their performance on instrumental measures of psychomotor slowing, dyskinesia, and neurological soft signs (NSS)-distinct motor domains affected across the psychosis spectrum.We also recruited a group of 70 matched healthy controls (HC) for comparison.All participants were also assessed with a resting-state functional connectivity analysis (rcfMRI).The resulting CHR group clusters and HCs were then compared on positive and negative symptoms, multiple cognitive domains, and cortical-striatal seed based resting state analysis.Results: Results of a 3-cluster solution suggest that there are subtypes of CHR individuals who show psychomotor slowing, average motor performance, and impairment on measures of dyskinesia as well as NSS domains for motor coordination, sequencing and sensory integration.The cluster of individuals showing dyskinesia and abnormal NSS also have more severe negative symptoms and impairment on a number of cognitive domains.Furthermore, the clusters of CHR individuals who show psychomotor