S24. JUVENILITY AND ADOLESCENCE ARE CRITICAL PERIODS OF VULNERABILITY TO PSYCHOTOGENIC EFFECT OF STRESS: RELEVANCE TO SCHIZOPHRENIA. (9th April 2019)

• Record Type: Journal Article
• Authors: Zhu, Xiyu; Gomes, Felipe; Grace, Anthony
• Is Part Of: Schizophrenia bulletin. Volume 45(2019)Supplement 2
• Page Start: S314
• Page End: S315
• Publication Date: 2019-04-09
• Subjects: Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbz020.569
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: Background: Our prior work on the methylazoxymethanol acetate (MAM) developmental model of schizophrenia showed that MAM-treated offspring during prepuberty have increased anxiety, hyper-responsivity to stress, and hyperactivity in the amygdala, prior to dopamine dysregulation. Furthermore, treating anxiety prepubertally prevented the emergence of hyperdopaminergic state in adulthood. These data suggest that early developmental disruption (genetic or environmental) might render individuals more susceptible to stress during critical time windows, during which unregulated stress can lead to the emergence of psychosis later in life. If this is true, one can further hypothesize that 1) sufficiently intense stress during vulnerable periods can lead to a similar hyperdopaminergic state in normal rats, and 2) reducing stress prepubertally can potentially prevent the manifestation of hyperdopaminergia in MAM rats. Methods: Pregnant Sprague Dawley rats were administered MAM at gestational day 17 and the offspring were tested as adults. In a subset of these rats, environmental enrichment (EE) was performed during postnatal day (PD) 21–40. In normal rats, stressors were administered in juvenility (PD21-30), adolescence (PD31-40), or adulthood (PD65-74). The stress paradigm consisted of 10-day footshock, 3 sessions of restraint stress, or a combination of both. A separate cohort of normal rats were treated with the histone deacetylase (HDAC) inhibitors, sodium valproate (VPA, 300mg/kg; i.p.) or SAHA (25mg/kg; i.p.), beginning 5 days before the stress paradigm and continuing until the end of the stress. Immunohistochemical analyses of parvalbumin (PV) interneurons and perineuronal nets (PNNs) were conducted, and dopamine neuron activity was recorded in vivo in the VTA. Results: Adult MAM rats exhibited increased DA neuron population activity in the VTA, manifested hyper-locomotion to amphetamine and disruption in novel object recognition. In contrast, early EE prevented this occurrence. Furthermore, combined stress during juvenility or adolescence in normal rats lead to changes similar to that observed in MAM rats, as well as altered maturation of PV interneurons in the ventral hippocampus. Of note, juvenile rats exhibited increased vulnerability to stress comparing to adolescent rats, as footshock alone induced MAM-like changes in adulthood only in this group. In contrast, stress during adulthood only led to a short-term hypodopaminergic state that is more consistent with a depression phenotype. However, in adult rats pre-treated with HDAC inhibitors which putatively reopen the developmental critical period, combined stress now led to a persistent loss of PV-PNN labeling in the ventral hippocampus, resulting in a hyperdopaminergic state in the VTA. Discussion: These data demonstrate the timing of stress as a critical factor determining the pathophysiological consequences. The fact that MAM can be circumvented via alleviation of stress prepubertally and that prepubertal stress can lead to a similar pathophysiology suggests that the predisposition to schizophrenia may be based on increased impact of stress prepubertally, when the PV neurons are in a vulnerable state. In contrast, in adults the PV neurons are protected by the PNNs, such that the same stressors now lead to a depressive state. However, reopening the critical period via histone deacetylase inhibition now causes adult rats to be susceptible to stress-induced schizophrenia-like hyperdopaminergic phenotype. This suggests that depression and schizophrenia may share a common predisposition in terms of increased stress susceptibility at different developmental stages, with the exact pathophysiology dependent on the timing of stress exposure.