Loss of Parvalbumin in the Hippocampus of MAM Schizophrenia Model Rats Is Attenuated by Peripubertal Diazepam

Du, Yijuan; Grace, Anthony A.

doi:10.1093/ijnp/pyw065

Cited by 33 publications

(20 citation statements)

References 30 publications

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“…Furthermore, the data suggests that this association was present the UHR subjects who went on to develop a psychotic disorder and absent in those who did not, although the study did not identify significant differences between UHR-NT and UHR-T subjects in either hippocampal rCBF or GABA 1 H-MRS alone. In light of recent evidence demonstrating that peripubertal pharmacological intervention on the GABAergic system in a rodent model of psychosis can block the development of striatal hyperdopaminergia in adulthood (Du and Grace, 2013, 2016; Gill et al , 2011), further research is warranted to investigate whether clinical interventions in the high-risk phase targeting this pathway may have the potential to reduce the risk of developing psychosis.…”

Section: Discussionmentioning

confidence: 99%

Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis

Modinos

Şimşek

Azis

et al. 2018

Neuropsychopharmacol

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Preclinical models propose that the onset of psychosis is associated with hippocampal hyperactivity, thought to be driven by cortical GABAergic interneuron dysfunction and disinhibition of pyramidal neurons. Recent neuroimaging studies suggest that resting hippocampal perfusion is increased in subjects at ultra-high risk (UHR) for psychosis, but how this may be related to GABA concentrations is unknown. The present study used a multimodal neuroimaging approach to address this issue in UHR subjects. Proton magnetic resonance spectroscopy and pulsed-continuous arterial spin labeling imaging were acquired to investigate the relationship between medial prefrontal (MPFC) GABA+ levels (including some contribution from macromolecules) and hippocampal regional cerebral blood flow (rCBF) in 36 individuals at UHR of psychosis, based on preclinical evidence that MPFC dysfunction is involved in hippocampal hyperactivity. The subjects were then clinically monitored for 2 years: during this period, 7 developed a psychotic disorder and 29 did not. At baseline, MPFC GABA+ levels were positively correlated with rCBF in the left hippocampus (region of interest analysis, p = .044 family-wise error corrected, FWE). This correlation in the left hippocampus was significantly different in UHR subjects who went on to develop psychosis relative to those who did not (p = .022 FWE), suggesting the absence of a correlation in the latter subgroup. These findings provide the first human evidence that MPFC GABA+ concentrations are related to resting hippocampal perfusion in the UHR state, and offer some support for a link between GABA levels and hippocampal function in the development of psychosis.

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Section: Discussionmentioning

confidence: 99%

Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis

Modinos

Şimşek

Azis

et al. 2018

Neuropsychopharmacol

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“…This in turn would lead to hippocampal hyperactivity and DA system dysregulation. We have shown previously that peripubertal administration of the benzodiazepine diazepam, can prevent the increased anxiety-like behavior and BLA hyperactivity, and normalize hyperdopaminergic activity typically present in adult MAM rats (166)(167)(168). These studies suggest that increased stress responsivity, particularly at crucial developmental stages, could lead to the emergence of psychosis in adults and that decreasing stress or other means of reducing vHipp activity during peripubertal period has the potential to circumvent the pathological processes that leads to DA system dysregulation (8).…”

Section: Impact Of Stress On Vta Dopamine Neuron Regulationmentioning

confidence: 89%

Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

2020

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Dysregulation of the dopamine system is central to many models of the pathophysiology of psychosis in schizophrenia. However, emerging evidence suggests that this dysregulation is driven by the disruption of upstream circuits that provide afferent control of midbrain dopamine neurons. Furthermore, stress can profoundly disrupt this regulatory circuit, particularly when it is presented at critical vulnerable prepubertal time points. This review will discuss the dopamine system and the circuits that regulate it, focusing on the hippocampus, medial prefrontal cortex, thalamic nuclei, and medial septum, and the impact of stress. A greater understanding of the regulation of the dopamine system and its disruption in schizophrenia may provide a more complete neurobiological framework to interpret clinical findings and develop novel treatments.

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“…We are unable to confirm if shipment stress had a similar impact in our study. Despite these limitations, many comparable studies on development and gestational adverse events have relied on the use of timed-pregnant dams (Lodge and Grace, 2001; Du and Grace, 2013, 2016a,b; Van den Eynde et al, 2014; Ballendine et al, 2015; Lins et al, 2018). Recently, Kentner et al (2019) highlighted that consideration of all MIA protocols will enable comprehensive understanding of their impacts on offspring outcomes.…”

Section: Discussionmentioning

confidence: 99%

Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats

Lins

Marks

Zabder

et al. 2019

eNeuro

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Sex differences are documented in psychiatric and neurological disorders, yet most preclinical animal research has been conducted in males only. There is a need to better understand of the nature of sex differences in brain disease in order to meet the needs of psychiatric patients. We present the behavior profile of adult female offspring produced using a maternal immune activation (MIA) model where pregnant rats receive an immune stimulant and the offspring typically show various abnormalities consistent with psychiatric illnesses such as schizophrenia and autism. The results in female offspring were compared to a previously published cohort of their male siblings ( Lins et al., 2018 ). We examined prepulse inhibition (PPI), sociability, MK-801-induced locomotor activity, crossmodal object recognition (CMOR), and oddity discrimination; behaviors relevant to the positive, negative, and cognitive symptoms of schizophrenia. No between-treatment differences in PPI or locomotor activity were noted. Tactile memory was observed in the control and treated female offspring, visual recognition memory was deficient in the polyinosinic:polycytidylic acid (polyI:C) offspring only, and both groups lacked crossmodal recognition. PolyI:C offspring were impaired in oddity preference and had reduced preference for a stranger conspecific in a sociability assay. Systemic maternal CXCL1, IL-6, and TNF-a levels 3 h after polyI:C treatment were determined, but no relationship was found between these cytokines and the behavior seen in the adult female offspring. Overall, female offspring of polyI:C-treated dams display an array of behavior abnormalities relevant to psychiatric illnesses such as schizophrenia similar to those previously reported in male rats.

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Loss of Parvalbumin in the Hippocampus of MAM Schizophrenia Model Rats Is Attenuated by Peripubertal Diazepam

Cited by 33 publications

References 30 publications

Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis

Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis

Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats

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