Aberrant Hippocampal Activity Underlies the Dopamine Dysregulation in an Animal Model of Schizophrenia

Lodge, Daniel J.; Grace, Anthony A.

doi:10.1523/jneurosci.2847-07.2007

Cited by 406 publications

(677 citation statements)

References 54 publications

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“…Therefore, a failure of the mPFC to regulate stress in the MAM-treated rat or in the prodromal stage of schizophrenia could contribute to pathological changes in the hippocampus observed in this disorder. It has been shown that activation of the amygdala, which occurs during stress, will lead to parvalbumin interneuron loss in the hippocampus (Berretta et al, 2001) and loss of hippocampal parvalbumin interneurons is proposed to lead to the DA hyper-responsivity in the MAM model (Lodge and Grace, 2007). Thus, a hypersensitivity to stress potentially secondary to decreased mPFC function could initiate a cascade of events during juvenile/adolescent stages to lead to hippocampal dysfunction and the emergence of the schizophrenia-like phenotype observed in the MAM model (Grace, 2004;Thompson et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

Zimmerman

Bellaire

Ewing

et al. 2013

Neuropsychopharmacol

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Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.

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Section: Discussionmentioning

confidence: 99%

Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

Zimmerman

Bellaire

Ewing

et al. 2013

Neuropsychopharmacol

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“…Hyperactivity of the mesolimbic dopamine system due to an altered regulation of the neurotransmitter dopamine has been suggested to be the major cause of symptoms in schizophrenia (Laruelle et al, 1999;Abi-Dargham et al, 2004;. Furthermore, human imaging and preclinical studies have suggested that hyperfunction of the dopamine system in schizophrenia stems from the hyperactivity of neurons in hippocampal subfields at rest (Medoff et al, 2001;Lodge and Grace, 2007;Shah and Lodge, 2013). The hippocampus regulates dopaminergic transmission through a multi-synaptic pathway involving the nucleus accumbens and ventral pallidum Lodge and Grace, 2011).…”

Section: Gaba-ergic Cell Grafts For Treating Schizophreniamentioning

confidence: 99%

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Shetty

Bates

2016

Brain Research

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Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gammaamino butyric acid positive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmission in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much consideration because of their ability for dispersion, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for easing neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer's disease and Parkinson's disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to considering the possible clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence-like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphasized.

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“…Studies in the maternal infection model, the DISC1 model, and prenatal exposure to methylazoxymethanol acetate (MAM), have shown that alterations of brain development during specific periods of pre or postnatal development produce discrete disruptions that lead to behavioral and neurochemical effects that include a decreased number of PVinterneurons (Hikida et al, 2007;Lodge and Grace, 2007;Meyer et al, 2007;Lodge et al, 2009). In the MAM model, where the mitotoxin is applied during interneuronal proliferation/migration stage, the number of PV-interneurons decreased in specific brain regions that correlated with alterations in oscillatory activity and decreased lateral inhibition in adulthood (Lodge et al, 2009).…”

Section: Neurodevelopmental Origins Of Schizophrenia: Activation Of Tmentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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Aberrant Hippocampal Activity Underlies the Dopamine Dysregulation in an Animal Model of Schizophrenia

Cited by 406 publications

References 54 publications

Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

Abnormal Stress Responsivity in a Rodent Developmental Disruption Model of Schizophrenia

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

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