Schizophrenia is among the most devastating of the psychiatric disorders, robbing more than 1% of the population worldwide of quality of life. While schizophrenia tends to run in families, the disorder is not completely genetically determined, and depends on an interaction with the environment. Among the most robust findings in schizophrenia is the nearly 30% decrease in parvalbumin (PV)-labeled GABAergic interneurons, particularly in the limbic hippocampus. This loss is paralleled by hyperactivity in the limbic hippocampus, which we have found in animal models drives increased dopamine system responsivity. It has been known that early life stress and anxiety often precedes the psychotic break, and moreover adolescent stress in rats is known to lead to PV neuron loss. Interestingly, stress can damage PV interneurons only when it occurs during adolescence; afterwards, the PV neurons develop perineuronal nets that protect them from damage. We have previously employed a developmental disruption model of schizophrenia based on gestational administration of a mitotoxin. Interestingly, these rats show increased anxiety and heightened stress response during adolescence, before the emergence of a dysregulated dopamine system. If we mimic this adolescent condition by combined stressors, we can induce a MAM-like phenotype in normal rats. Therefore, we posit that susceptibility to stressors that occur prior to the formation of perineuronal nets lead to damage of vHipp PV interneurons, vHipp hyperactivity, and the emergence of the hyperdopaminergic state in the adult. We further suggest that the increased stress responsivity in susceptible adolescents may be due to a failure of the prelimbic prefrontal cortex to limit the impact of stress. Finally, given that females have a later onset of schizophrenia and less pathology, we posit that adolescent stress will not impact female rats to the degree seen in males. We will assess this model via the following Specific Aims: 1) Determine the development of stress-induced pathology in normal adult male and female rats, and how this correlates with PNN and PV interneuron staining; 2) Determine the role of prepubertal plPFC lesions and BLA activity on stress reactivity, anxiety, and footshock-induced PV loss/DA hyperresponsivity in peripubertal and adult rats, and the role of plPFC inhibition of the BLA in the pathology; and 3) Examine whether re-opening the critical period or PNN disruption in the adult can cause the rat to regain stressor-induced PV neuron loss and DA system hyperresponsivity, and if this is driven by the BLA. In this way, we hope to be able to provide a link between genetic/gestational susceptibility and environmental factors that occur early in life, initiating a cascade of events that lead to the emergence of schizophrenia later in life. This will provide insights not only into the pathophysiology of schizophrenia, but also into establishing predictive criteria for psychosis susceptibility and ultimately into prevention.

Public Health Relevance

Schizophrenia is among the most devastating psychiatric disorders, striking 1% of the population at a time when they are becoming independent and starting their careers; nonetheless, little is known about the cause of this disorder or how it can be prevented. Based on our previous work, we have identified a mechanism by which susceptibility to schizophrenia combined with early life stress can lead to selective loss of a specific neuron type at a stage of development in which it is particularly vulnerable. By studying the factors that link susceptibility to stress-induced damage, we hope to better understand the cause of this disorder, and more importantly design methods to predict susceptibility and intervene in a way that may prevent the emergence of schizophrenia later in life.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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University of Pittsburgh
Schools of Arts and Sciences
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Gomes, Felipe V; Edelson, Jessica R; Volk, David W et al. (2018) Altered brain cannabinoid 1 receptor mRNA expression across postnatal development in the MAM model of schizophrenia. Schizophr Res 201:254-260
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
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
Sonnenschein, Susan F; Gill, Kathryn M; Grace, Anthony A (2018) State-dependent effects of the D2 partial agonist aripiprazole on dopamine neuron activity in the MAM neurodevelopmental model of schizophrenia. Neuropsychopharmacology :
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
Zimmerman, Eric C; Grace, Anthony A (2018) Prefrontal cortex modulates firing pattern in the nucleus reuniens of the midline thalamus via distinct corticothalamic pathways. Eur J Neurosci 48:3255-3272
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
Lipski, Witold J; Dibble, Sofia M; Rinaman, Linda et al. (2017) Psychogenic Stress Activates C-Fos in Nucleus Accumbens-Projecting Neurons of the Hippocampal Ventral Subiculum. Int J Neuropsychopharmacol 20:855-860
Grace, Anthony A (2017) Gilles de la Tourette's and the Disruption of Interneuron-Mediated Synchrony : Comments on: Hashemiyoon, R., Kuhn, J., Visser-Vandewalle, V. Brain Topography (2016). DOI 10.1007/s10548-016-0525-z. Brain Topogr 30:1-2

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