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

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2007; 27(42):11424-30. DOI: 10.1523/JNEUROSCI.2847-07.2007
Source: PubMed


Evidence supports a dysregulation of subcortical dopamine (DA) system function as a common etiology of psychosis; however, the factors responsible for this aberrant DA system responsivity have not been delineated. Here, we demonstrate in an animal model of schizophrenia that a pathologically enhanced drive from the ventral hippocampus (vHipp) can result in aberrant dopamine neuron signaling. Adult rats in which development was disrupted by prenatal methylazoxymethanol acetate (MAM) administration display a significantly greater number of spontaneously firing ventral tegmental DA neurons. This appears to be a consequence of excessive hippocampal activity because, in MAM-treated rats, vHipp inactivation completely reversed the elevated DA neuron population activity and also normalized the augmented amphetamine-induced locomotor behavior. These data provide a direct link between hippocampal dysfunction and the hyper-responsivity of the DA system that is believed to underlie the augmented response to amphetamine in animal models and psychosis in schizophrenia patients.

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Available from: Anthony Grace, Oct 06, 2015
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    • "Administration of MAM, a DNA chelating agent, to pregnant dams at 15 GD or earlier disrupts normal fetal brain development and induces gross neurodevelopmental abnormalities both in the macro-and microstructure, particularly in cortical regions, and microcephaly (Singh, 1980;Jongen-Relo et al., 2004). When MAM is administered at a later stage during pregnancy (GD 17), less severe abnormalities with hyperdopaminergia were reported (Lodge and Grace, 2007;Du and Grace, 2013). On the other hand, maternal immune activation models recapitulate the effects of a maternal viral infection, activate microglia and cytokines production. "
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    ABSTRACT: Background. In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area (VTA) dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia.Methods. Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid [poly(I:C)] in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in VTA were studied by in vivo electrophysiology.Results. Poly(I:C)-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In poly(I:C) rats dopamine neurons showed reduced spontaneously firing rate and population activity.Conclusions. These results confirm that maternal immune activation severely impairs dopamine system and that the poly(I:C) model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.
    Full-text · Article · Jan 2016 · The International Journal of Neuropsychopharmacology
    • "Another version, sPAL, is identical to dPAL except that the two stimuli displayed in each trial are identical. We used the dPAL version of the task because it is more sensitive to pharmacological manipulations of the hippocampus (Talpos et al. 2009), an area implicated in schizophrenia pathology (Wood et al. 2002; Lodge and Grace 2007; Jodo 2013). In dPAL, rats are presented with two of the three images in each trial in a pseudorandom order. "
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    ABSTRACT: Rationale New pharmacological treatments for the cognitive deficits in schizophrenia are needed. Tetrahydroprotoberberines, such as govadine, are one class of compounds with dopaminergic activities that may be useful in treating some aspects of the cognitive symptoms of the disorder. Objective The objective of the present studies was to test the effects of the d- and l-enantiomers of govadine on the impairment in a paired-associate learning (PAL) task produced by acute MK-801 in rats. We also assessed effects of the typical antipsychotic haloperidol as a comparator compound. Methods MK-801 (0.05, 0.1, 0.15, and 0.2 mg/kg), d- and l-govadine (0.3, 1.0, and 3.0 mg/kg), and haloperidol (0.05, 0.1, and 0.25 mg/kg) were administered acutely to rats well trained on the PAL task in touchscreen-equipped operant conditioning chambers. Results Acute MK-801 impaired performance of PAL in a dose-dependent manner by reducing accuracy and increasing correction trials. l-Govadine (1.0 mg/kg), but not d-govadine, blocked the disruptive effects of MK-801 (0.15 mg/kg) on PAL. Haloperidol failed to affect the MK-801-induced disruption of PAL. Higher doses of l-govadine and haloperidol dramatically impaired performance of the task which confounded interpretation of cognitive outcomes. Conclusion l-Govadine appears unique in its ability to improve performance of the MK-801-induced impairment in the PAL task. This behavioral effect may relate the ability of l-govadine to antagonize dopamine D2 receptors while also promoting dopamine efflux. Future research should further characterize the role of the dopamine system in the rodent PAL task to elucidate the mechanisms of its pro-cognitive effects.
    No preview · Article · Sep 2015 · Psychopharmacology
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    • "chizophrenia ( Moore et al . 2006 ; Lodge and Grace . 2009 ) . Changes in the hippocampus include volume reduction , aberrant neuronal or - ganisation and excitability , deficits in synaptic transmission and synaptic plasticity , and abnormal neuronal oscillatory ac - tivity ( Gourevitch et al . 2004 ; Moore et al . 2006 ; Penschuck et al . 2006 ; Lodge and Grace . 2007 ; Matricon et al . 2010 ; Chin et al . 2011 ; Hradetzky et al . 2012 ; Phillips et al . 2012a , b ; Sanderson et al . 2012 ; Snyder et al . 2013 ) . Alongside these robust anatomical and physiological alterations , a number of studies have looked at the effects of MAM E17 treatment in behavioural paradigms assessing hippocampus - depend"
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    ABSTRACT: Adult rats exposed to methylazoxymethanol acetate (MAM) at embryonic day 17 (E17) display robust pathological alterations in the hippocampus. However, discrepancies exist in the literature regarding the behavioural effects of this pre-natal manipulation. Therefore, a systematic assessment of MAM E17-induced behavioural alterations was conducted using a battery of dorsal and ventral hippocampus-dependent tests. Compared to saline controls, MAM E17-treated rats displayed deficits in spatial reference memory in both the aversive hidden platform watermaze task and an appetitive Y-maze task. Deficits in the spatial reference memory watermaze task were replicated across three different cohorts and two laboratories. In contrast, there was little, or no, effect on the non-spatial, visible platform watermaze task or an appetitive, non-spatial, visual discrimination task, respectively. MAM rats were also impaired in the spatial novelty preference task which assesses short-term memory, and displayed reduced anxiety levels in the elevated plus maze task. Thus, MAM E17 administration resulted in abnormal spatial information processing and reduced anxiety in a number of hippocampus-dependent behavioural tests, paralleling the effects of dorsal and ventral hippocampal lesions, respectively. These findings corroborate recent pathological and physiological studies, further highlighting the usefulness of MAM E17 as a model of hippocampal dysfunction in at least some aspects of schizophrenia.
    Full-text · Article · Jan 2015 · Psychopharmacology
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