40. EARLY INTERVENTION IS EFFECTIVE IN HALTING DEVELOPMENTAL NEUROPATHOLOGY AND BEHAVIORAL DEFICITS: LESSONS FROM MODEL RODENTS. (9th April 2019)

• Record Type: Journal Article
• Authors: Weiner, Ina
• Is Part Of: Schizophrenia bulletin. Volume 45(2019)Supplement 2
• Page Start: S153
• Page End: S153
• Publication Date: 2019-04-09
• Subjects: Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbz022.163
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: The recognition that schizophrenia is associated with early brain insult and that its onset in adolescence/early adulthood is preceded by progressive brain changes, has raised the exciting notion that pre-diagnostic intervention may halt neuroprogression and symptom emergence, but the topic remains controversial. We will demonstrate that early intervention can normalize a wide range of schizophrenia-relevant neural abnormalities induced in model rodents across development, as well as prevent the emergence of behavioral pathology. Zheng Li will show that dopamine D2 receptors regulate the maturation of dendritic spines during adolescence. In mice deficient for DTNBP1, a gene encoding dysbindin-1 protein, the number of dendritic spines is reduced in adolescent, but not in adult mice. This effect is mediated by over-expression of dopamine D2 receptors on the cell surface, which leads to GluN2B internalization and cAMP reduction. The transient decrease of dendritic spines during adolescence causes mis-wiring of neural connections and impairment of spatial working memory in adulthood. These defects can be prevented with D2 receptor blockers administered only during adolescence. Wen-Jun Gao will describe the mechanisms underlying NMDAR hypofunction development during the early stage of development. He will further show that prefrontal NMDAR hypofunction and PFC-dependent learning and memory deficits in the methylazoxymethanol-acetate (MAM) rat model of schizophrenia are prevented by mGluR2/3 modulator or GSK3b inhibitor given to juvenile, but not adult, offspring. These findings highlight the glutamatergic dysfunction as a target for early intervention in schizophrenia. Ina Weiner will report that the efficacy of risperidone or clozapine in preventing volumetric abnormalities and accompanying behavioral deficits in female rats prenatally exposed to a viral mimic poly-I:C is a function of time of administration window, with highest efficacy in adolescence and loss of efficacy in adulthood, as well as the drug, with risperidone being more effective than clozapine. The results with both drugs demonstrate that prevention of behavioral abnormalities requires normalization of structural deficits and must be implemented prior to the emergence of behavioral abnormalities. Daniel Lodge will demonstrate the feasibility of 'gene therapy' targeting vHipp GABAergic function to reverse physiological and behavioral deficits in the MAM model. Specifically, overexpression of the a5 subunit of the GABAA receptor was able to normalize hippocampal hyperactivity as well as downstream alterations in VTA dopamine neuron function, suggested to contribute to positive symptoms. This approach was also able to attenuate behavioral deficits in cognitive flexibility. These results suggest that restoring tonic GABAergic signaling in the vHipp improves schizophrenia-like deficits in a rodent model. Collectively, the data demonstrate that the neurodevelopmentally compromised brain is remarkably plastic until "symptom" emergence in adolescence/early adulthood, and that intervention during this window is trans-risk factors, trans-symptomatic, and highly effective, achieved with diverse insults, manipulations, and neuropsychopathological outcomes.