A Deficit in Parvalbumin-Expressing Interneurons in the Hippocampus Leads to Physiological and Behavioral Phenotypes Relevant to Schizophrenia in a Genetic Mouse Model
Creators: Gilani, Ahmed Ijaz
Publisher: name: Columbia University
Year: 2014
Subjects: Hippocampus (Brain)
Schizophrenia
Interneurons
Psychobiology
Psychophysiology

description: Hippocampal GABAergic interneuron deficits are implicated in the pathophysiology of schizophrenia. Postmortem histological analyses show alteration in number and/or function of parvalbumin-expressing (PV+) GABAergic interneurons in the cerebral cortex of these patients. A parallel line of research using functional imaging of cerebral blood flow or volume has shown that hyperactivity of the hippocampus may contribute to psychotic symptoms as well as cognitive deficits in schizophrenia. It is not known if changes in GABA transmission, particularly in the number and function of PV+ interneurons, are causally related to hippocampal hyperactivity and expression of behavioral and cognitive abnormalities in schizophrenia. To help answer this question, we used genetic mouse models with deficits in cortical GABAergic interneuron development to test the hypothesis that a selective deficit in PV+ interneurons in the hippocampus can lead to schizophrenia relevant phenotypes such as hippocampal hyperactivity, dysregulation of the mesolimbic dopamine system, enhanced psychomotor responsiveness to amphetamine, and disruption of hippocampal dependent cognition. Here I describe my studies primarily on a mouse model with a deletion of the cell-cycle gene cyclin D2 (cD2 null). This mutation disrupts interneuron development in the medial ganglionic eminence (MGE), leading to a partial and selective deficit in PV+ interneurons in the neocortex and the hippocampus. I show that the cD2 null mouse shows regionally heterogeneous, persistent structural and functional deficit in PV+ interneurons, with a relatively larger and more functional deficit in the hippocampus. The GABAergic deficit in the hippocampus is associated with signs of disinhibition, such as increased cerebral blood volume as found by functional magnetic resonance imaging (fMRI).Upon establishing the evidence for hippocampal disinhibition in the cyclin D2 null mouse, I examined the relationship between this disinhibition and two areas of neural function know to be altered in psychosis and schizophrenia: Mesostriatal DA system function and hippocampus-mediated cognition. I found that the cD2 null mice showed increased dopamine population activity in the ventral tegmental area and enhanced psychomotor response to amphetamine. The latter was eliminated by a partial lesion of the ventral hippocampus, indicating hippocampal disinhibition as the driver of DA neuron dysregulation. In addition, cD2 null mice showed deficits in cognitive functions that recruit and depend on the hippocampus, such as the contextual and cued fear conditioning. Lastly, to test for a causal relationship between the PV+ interneuron deficit in the hippocampus, and the abnormalities in hippocampal metabolism, imaging phenotype, the mesolimbic dopamine dysfunction and contextual learning and memory, I examined the effects of replacing GABAergic interneurons to the hippocampus. I used transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) into the adult hippocampus of cyclin D2 null mutants. MGE-derived progenitor cells developed into structurally and functionally mature PV+ and other GABAergic cells, and normalized hippocampal hypermetabolism. In addition, the MGE transplants normalized VTA dopamine cell activity, normalized amphetamine sensitivity and improved hippocampus-dependent learning and memory. Taken together, these studies establish the plausibility of a causal relationship between hippocampal PV+ interneuron pathology and psychosis-relevant pathophysiological and cognitive phenotypes. Moreover, they provide a rationale for limbic cortical GABAergic-interneuron-targeted treatment strategies in psychotic disorders.