3.1 PREPUBERTAL STRESS AND AMYGDALA-HIPPOCAMPAL OVERDRIVE IN THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA: ALLEVIATION BY EARLY ENVIRONMENTAL ENRICHMENT. (9th April 2019)

• Record Type: Journal Article
• Authors: Grace, Anthony; Gomes, Felipe; Zhu, Xiyu
• Is Part Of: Schizophrenia bulletin. Volume 45(2019)Supplement 2
• Page Start: S89
• Page End: S90
• Publication Date: 2019-04-09
• Subjects: Schizophrenia -- Periodicals; Schizophrenia -- Research -- Periodicals; 616.898005
• DOI: 10.1093/schbul/sbz022.003
• Languages: English
• ISSNs: 0586-7614

Abstract

Abstract: Background: The combination of genetic susceptibility and environmental factors are believed to underlie susceptibility to schizophrenia. Stress is known to activate the basolateral amygdala and, via its projections to the hippocampus, induce parvalbumin (PV) interneuron loss. This in turn leads to dopamine system overdrive thought to underlie psychosis. We have shown in the MAM developmental disruption model that increased anxiety prepubertally can drive this circuit to lead to interneuron loss, and moreover combined stressors in normal rats prepubertally can mimic this effect, which is exacerbated when prelimbic prefrontal cortical control of the amygdala is disrupted. We now show that the timing of the insult is critical, that reopening the critical period in the adult can lead to a similar condition, and finally relieving stress prepubertally via environmental enrichment can circumvent the later transition to the hyperdopaminergic state. Methods: Pregnant rats were administered methylazoxymethanol acetate (MAM) at gestational day 17 and the offspring tested as adults. In a subset of these rats, exposure to environmental enrichment was performed at postnatal day (PD) 21–40. Normal rats were also exposed to 10 days footshock and 3 sessions of restraint stress either during PD 31–40 or 65–75 and tested 1–2 weeks or 5–6 weeks after the stressor. In a subset of adult stress rats, rats were exposed to the histone deacetylase inhibitors valproic acid (VPA) or SAHA beginning 5 days before the stress and continuing through the stress protocol. Immunohistochemical detection of PV neurons and perineuronal nets (PNN) were conducted, and pyramidal and dopamine neuron activity was recorded in vivo in the hippocampus and VTA respectively. Results: Rats exposed to MAM gestationally were found to exhibit increased VTA DA neuron population activity, hyper-locomotion to amphetamine, and disruption in novel object recognition as adults. In contrast, exposure to either the antianxiety agent diazepam (PD31-40) or environmental enrichment (PD 21–40) prepubertally prevented this occurrence. Furthermore, combined footshock + restraint administered at PD31-40 in normal rats lead to a similar pathology in the adult. In contrast, combined stressors administered at adults (PD65-75) led to a short-term attenuation of DA activity similar to that observed in depression models. However, if the developmental critical period was re-opened in adults using either VPA or SAHA to resemble the prepubertal state, combined stressors now led to a persistent loss of PV-PNN labeling in the hippocampus, resulting in persistent hippocampal hyperactivity and a persistent increase in VTA DA neuron activity. Conclusions: These data demonstrate that the timing of environmental stress is critical in 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 is based on increased impact of stress prepubertally, when the PV neurons are in a vulnerable state. In contrast, in the adult when PV neurons have a protective PNN, the same stressors now lead to a depressive state. However, reopening the critical period via histone deacetylase inhibition now causes the adult rat to be susceptible to stress-induced hyperdopaminergic phenotype. This suggests that depression and schizophrenia may share a common genetic predisposition leading to increased stress susceptibility at different developmental stages, with the pathophysiology dependent on the timing of the stressor.