Aberrant Hippocampal Activity Underlies the Dopamine Dysregulation in an Animal Model of Schizophrenia
ABSTRACT 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.
- SourceAvailable from: Sanna K Janhunen
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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"
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.Psychopharmacology 01/2015; DOI:10.1007/s00213-014-3862-1 · 3.99 Impact Factor
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- "The impact of MAM on the developing brain is nonspecific but a comprehensive review of identified changes is available (Lodge and Grace, 2009). Among brain regions affected by MAM are the prefrontal cortex (Esmaeili and Grace, 2013), nucleus accumbens (Perez and Lodge, 2012), ventral hippocampus (Lodge and Grace, 2007), and the ventral subiculum-nucleus accumbens-prefrontal cortex circuit (Belujon et al., 2014). Histological assessment of hippocampi in GD17- MAM animals shows morphological deficiencies (Matricon et al., 2010) that we have confirmed in unpublished studies. "
ABSTRACT: Despite substantial effort and immense need, the treatment options for major neuropsychiatric illnesses like schizophrenia are limited and largely ineffective at improving the most debilitating cognitive symptoms that are central to mental illness. These symptoms include cognitive control deficits, the inability to selectively use information that is currently relevant and ignore what is currently irrelevant. Contemporary attempts to accelerate progress are in part founded on an effort to reconceptualize neuropsychiatric illness as a disorder of neural development. This neuro-developmental framework emphasizes abnormal neural circuits on the one hand, and on the other, it suggests there are therapeutic opportunities to exploit the developmental processes of excitatory neuron pruning, inhibitory neuron proliferation, elaboration of myelination, and other circuit refinements that extend through adolescence and into early adulthood. We have crafted a preclinical research program aimed at cognition failures that may be relevant to mental illness. By working with a variety of neurodevelopmental rodent models, we strive to identify a common pathophysiology that underlies cognitive control failure as well as a common strategy for improving cognition in the face of neural circuit abnormalities. Here we review our work to characterize cognitive control deficits in rats with a neonatal ventral hippocampus lesion and rats that were exposed to Methylazoxymethanol acetate (MAM) in utero. We review our findings as they pertain to early developmental processes, including neurogenesis, as well as the power of cognitive experience to refine neural circuit function within the mature and maturing brain's cognitive circuitry.Frontiers in Neuroscience 06/2014; 8:153. DOI:10.3389/fnins.2014.00153 · 3.70 Impact Factor
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- "published online 2 July 2014 INTRODUCTION Abnormalities in glutamatergic neurotransmission are thought to have a key role in the pathophysiology of schizophrenia (Goff and Coyle, 2001; Javitt and Zukin, 1991; Olney and Farber, 1995), and this is supported by evidence from postmortem, neuroimaging, and genetic studies (Harrison and Weinberger, 2005; Konradi and Heckers, 2003; Pilowsky et al, 2006). In experimental animals, administration of antagonists at the N-methyl-D-aspartate (NMDA) glutamate receptor complex leads to injury to cortical neurons (Sharp et al, 2001) and overactivity of medial temporal glutamatergic projections induces striatal hyperdopaminergia (Lodge and Grace, 2007). Glutamatergic dysfunction could thus contribute to the loss of gray matter and dopamine dysfunction that are robust features of schizophrenia (Carlsson et al, 2001; Javitt, 2007; Olney et al, 1999). "
ABSTRACT: Alterations in brain glutamate levels may be associated with psychosis risk, but the relationship to clinical outcome in at risk individuals is unknown. Glutamate concentration was measured in the left thalamus and anterior cingulate cortex (ACC) using 3 Tesla proton magnetic resonance spectroscopy in 75 participants at Ultra High Risk (UHR) of psychosis and 56 healthy controls. The severity of attenuated positive symptoms and overall functioning was assessed. Measures were repeated in 51 UHR and 33 Control subjects after a mean of 18 months. UHR subjects were allocated to either remission (no longer meeting UHR criteria) or non-remission (meeting UHR or psychosis criteria) status on follow-up assessment. Thalamic glutamate levels at presentation were lower in the UHR non-remission (N=29) compared to the remission group (N=22) (t(49)=3.03; P=0.004), and were associated with an increase in the severity of total positive symptoms over time (r=-0.33; df=47; P=0.02), most notably abnormal thought content (r=-0.442; df=47; P=0.003). In the UHR group, ACC glutamate levels were lower at follow-up compared to baseline (F(80)=4.28; P=0.04). These findings suggest that measures of brain glutamate function may be useful as predictors of clinical outcome in individuals at high risk of psychosis.Neuropsychopharmacology accepted article preview online, 11 June 2014; doi:10.1038/npp.2014.143.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.143 · 8.68 Impact Factor