A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia

Abstract

Postmortem studies in schizophrenia patients have demonstrated robust alterations in GABAergic markers throughout the neuraxis. It has been suggested that these alterations are restricted to subpopulations of interneurons, such as those containing the calcium binding protein parvalbumin. Indeed, a reduction in parvalbumin expression is a consistent observation in human postmortem studies, as well as, in a wide and diverse variety of animal models. However, it still remains to be determined whether this decrease in parvalbumin expression contributes to, or is a consequence of the disease. Here we utilize lentiviral delivered shRNA and demonstrate that a selective reduction in parvalbumin mRNA expression induces hyperactivity within the ventral hippocampus. In addition, we observe downstream increases in dopamine neuron population activity without changes in average firing rate or percent burst firing. These changes in dopamine neuron activity were associated with an enhanced locomotor response to amphetamine administration. These data therefore demonstrate that a reduction in ventral hippocampal parvalbumin expression is sufficient, in and of itself, to induce an augmented dopamine system function and behavioral hyper-responsivity to amphetamine, implicating a potential key role for parvalbumin in the pathophysiology of schizophrenia.

Keywords: Dopamine; Hippocampus; Parvalbumin; Schizophrenia.

Figure 1

Lentiviral administration of parvalbumin (PV) shRNA decreases the number of PV positive interneurons in the ventral hippocampus. Images in A & B represent PV positive neurons (red) as determined by immunohistochemistry. The graph in C depicts the quantification of computer assisted cell counts throughout the ventral extent of the hippocampus. † represents p<0.05, Student’s t-test.

Figure 2

Lentiviral administration of parvalbumin (PV) shRNA increases hippocampal and dopamine neuron activity. Putative pyramidal neurons throughout the hippocampus were recorded (A) and demonstrated significantly greater activity in PV shRNA treated rats. Downstream increases in dopamine neuron population activity (B) were also observed without significant changes in average firing rate (C) or burst firing (D). † represents p<0.05, Mann Whitney Rank Sum test.

Figure 3

Lentiviral administration of parvalbumin (PV) shRNA augments the locomotor response to amphetamine. Baseline locomotor activity was not significantly affected by vHipp PV knockdown (black squares) relative to control (non-silencing shRNA: Grey circles). In contrast, the locomotor response to both low (0.5mg/kg) and high (2.0mg/kg) doses of amphetamine were significantly enhanced demonstrating that a decrease in vHipp PV expression is sufficient to induce behavioral alterations consistent with those observed in schizophrenia. † represents p<0.05, 2-way ANOVA.