Recent studies in the field of schizophrenia have provided support for the theory that dysregulation of the mesolimbic dopamine system, thought to underlie positive symptoms of the disease, stems from hyperactivity of the hippocampus. Human imaging studies and experiments done in rodent models of the disease do indeed illustrate this phenomenon. We believe hippocampal hyperactivity is a result of a lack of GABAergic inhibitory control in this region. Consistent with this hypothesis, a marked decrease of parvalbumin positive interneurons is observed throughout the frontal cortices and hippocampi of patients and rodent models. Specifically, GABAergic interneuron function decreases may be the cause of the aberrant hippocampal output. Rodent students done in the MAM model, a verified gestation disruption model of schizophrenia, demonstrate that by inhibiting aberrant ventral hippocampal activity, via TTX inactivation, we observe a restoration of dopamine system function. Here we will utilize a novel procedure to restore ventral hippocampal interneuron function by transplanting GABAergic neurons from the medial ganglionic eminence of embryonic rats into the ventral hippocampus of post-pubertal MAM-treated rats. Cells from this region have been shown to differentiate into mature interneurons and may act to normalize aberrant dopamine transmission and behaviors, providing a novel therapeutic target. We plan to evaluate the effects of MGE cell transplantation in MAM-treated rats with the following Specific Aims: 1) determining the effects of GFP+ vHipp GABAergic precursor cell transplant on ventral hippocampal and dopamine neuron activity and 2) determining whether GFP+ vHipp GABAergic precursor cell transplant will reverse behaviors associated with the positive, negative, and cognitive deficits seen MAM-treated rats. Data collected from the proposed studies will provide evidence to further understand the disorder, as well as, provide a novel target for the pharmacology intervention of schizophrenia.
Schizophrenia is a debilitating disease affecting about 1% of the population with limited treatment options. Recent advances from clinical and pre-clinical studies suggest that a pathological decrease in GABAergic interneuron function may underlie the symptoms of the schizophrenia. In this project we aim to restore interneuron function in an attempt to better understand disease pathophysiology and improve therapeutic targets.
|Perez, Stephanie M; Aguilar, David D; Neary, Jennifer L et al. (2016) Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia. Neuropsychopharmacology 41:477-86|
|Boley, Angela M; Perez, Stephanie M; Lodge, Daniel J (2014) A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia. Schizophr Res 157:238-43|
|Perez, Stephanie M; Chen, Li; Lodge, Daniel J (2014) Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia. Psychoneuroendocrinology 47:88-97|
|Perez, Stephanie M; Carreno, Flavia R; Frazer, Alan et al. (2014) Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia. J Neurosci 34:9261-7|
|Perez, S M; Lodge, D J (2013) Hippocampal interneuron transplants reverse aberrant dopamine system function and behavior in a rodent model of schizophrenia. Mol Psychiatry 18:1193-8|