Studies conducted over the previous funding period were aimed at examining vSub-mPFC modulation of the NAc and how this affects dopamine (DA) neuron activity, and how this is disrupted in the MAM rat model of schizophrenia. Using the MAM model of schizophrenia, we found that these rats show hyper-responsivity to amphetamine that correlates with an increase in the number of dopamine neurons firing (i.e., dopamine neuron population activity). Moreover, this increase Is due to increased drive from the ventral subiculum of the hippocampus (vSub);a region that also shows decreased parvalbumin interneuron labeling. Forthe next 5 years ofthis grant, we plan to focus on several unique findings made during the initial funding period. Specifically, we plan to focus on plasticity and interactions of the hippocampus/prefrontal cortex interactions within the nucleus accumbens, and to now include the amygdala into this interaction based on growing evidence of Its importance in schizophrenia;to test whether the increase in hippocampal activity is correlated with a loss of parvalbumin interneurons or instead to a decrease in parvalbumin expression;to examine novel treatments for schizophrenia using our animal model;and to examine whether peripubertal inten/ention can prevent the transition to schizophrenia, and conversely whether stress during this interval will exacerbate the schizophrenia-like pathological changes. This will be accomplished by the following specific aims: 1. Examine how afferent drive and synaptic plasticity is altered in the MAM model within the vSub-mPFCamygdala- NAc circuit;2. Examine whether the increased vSub activity is due to loss of parvalbumin interneurons or decreased parvalbumin expression due to decreased interneuron drive, when this occurs in development, and if this can be reversed. 3. Examine potential novel treatments for schizophrenia based on restoration of function in the MAM model. 4. Examine whether peripubertal intervention can exacerbate or prevent the transition to experimental psychosis/pathophysiology in the MAM rat. We hope that this will provide novel information regarding the cellular dynamics underlying the pathological changes that occur In schizophrenia, novel targets for more effective treatment, and the potential for a preventive strategy.

Public Health Relevance

; Due to the lack of understanding ofthe cellular basis of schizophrenia, current treatment strategies have not been particularly effective in treating this disorder. Using a rat developmental model of schizophrenia that mimics many aspects of the disorder, we discovered the potential cellular basis for the psychotic symptoms of this disorder, which has led to new targets for more effectively treating schizophrenia as well as a potential strategy for prevention of the transition to schizophrenia in susceptible individuals.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Meinecke, Douglas L
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University of Pittsburgh
Schools of Arts and Sciences
United States
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Uliana, Daniela L; Resstel, Leonardo B M; Grace, Anthony A (2018) Fear extinction disruption in a developmental rodent model of schizophrenia correlates with an impairment in basolateral amygdala-medial prefrontal cortex plasticity. Neuropsychopharmacology 43:2459-2467
Neves, Gilda A; Grace, Anthony A (2018) ?7 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia. Neuropsychopharmacology 43:1712-1720
Bortz, David M; Grace, Anthony A (2018) Medial septum activation produces opposite effects on dopamine neuron activity in the ventral tegmental area and substantia nigra in MAM vs. normal rats. NPJ Schizophr 4:17
Gill, Kathryn M; Miller, Sarah A; Grace, Anthony A (2018) Impaired contextual fear-conditioning in MAM rodent model of schizophrenia. Schizophr Res 195:343-352
Bortz, David M; Grace, Anthony A (2018) Medial septum differentially regulates dopamine neuron activity in the rat ventral tegmental area and substantia nigra via distinct pathways. Neuropsychopharmacology 43:2093-2100
Zhu, Xiyu; Gomes, Felipe V; Grace, Anthony A (2017) The methylazoxymethanol acetate rat model: molecular and epigenetic effect in the developing prefrontal cortex: An Editorial Highlight for 'Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM J Neurochem 143:264-267
Grace, Anthony A (2017) Dopamine System Dysregulation and the Pathophysiology of Schizophrenia: Insights From the Methylazoxymethanol Acetate Model. Biol Psychiatry 81:5-8
Zimmerman, Eric C; Grace, Anthony A (2016) The Nucleus Reuniens of the Midline Thalamus Gates Prefrontal-Hippocampal Modulation of Ventral Tegmental Area Dopamine Neuron Activity. J Neurosci 36:8977-84
Gomes, Felipe V; Rincón-Cortés, Millie; Grace, Anthony A (2016) Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model. Neurosci Biobehav Rev 70:260-270
Harun, Rashed; Hare, Kristin M; Brough, Elizabeth M et al. (2016) Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo. J Neurochem 136:1270-1283

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