Schizophrenia patients exhibit increased hippocampal activity that is correlated with positive symptoms. While the cause of this hippocampal hyperactivity has not been demonstrated, it likely involves a decrease in GABAergic signaling. Thus, we posit that restoring GABAergic function may provide a novel therapeutic approach for the treatment of schizophrenia. It has been demonstrated that transplanted GABAergic precursor cells from the medial ganglionic eminence (MGE) can migrate and differentiate into mature interneurons. Here, we demonstrate that ventral hippocampal (vHipp) MGE transplants can restore hippocampal function and normalize downstream dopamine neuron activity in a rodent model of schizophrenia. Furthermore, MGE transplants also reverse the hyper-responsive locomotor response to amphetamine. Taken together, these data demonstrate that restoring interneuron function reverses neurophysiological and behavioral deficits in a rodent model of schizophrenia and moreover, demonstrate the feasibility of a neuronal transplant procedure as a potential novel therapeutic approach for the treatment of schizophrenia.

Leptin receptors (Lepr) are expressed on midbrain dopamine neurons. However, the specific role of Lepr signaling in dopamine neurons remains to be clarified. In the present study, we generated a line of conditional knockout mice lacking functional leptin receptors selectively on dopamine neurons (LeprDAT-Cre). These mice exhibit normal body weight and feeding. Behaviorally, LeprDAT-Cre mice display an anxiogenic-like phenotype in the elevated plus-maze, light-dark box, social interaction and novelty-suppressed feeding tests. Depression-related behaviors in the chronic stress-induced anhedonia, forced swim and tail-suspension tests were not affected by deletion of Lepr in dopamine neurons. In vivo electrophysiological recordings of dopamine neurons in the ventral tegmental area (VTA) revealed an increase in burst firing in LeprDAT-Cre mice. Moreover, blockade of D1-dependent dopamine transmission in the central amygdala by local microinjection of the D1 antagonist SCH23390 attenuated the anxiogenic phenotype of LeprDAT-Cre mice. These findings suggest that leptin receptor signaling in midbrain dopamine neurons has a crucial role for the expression of anxiety and for the dopamine modulation of amygdala function.

Summary Subcortical dopamine system dysregulation has been suggested to underlie the positive symptoms of schizophrenia. Recent preclinical investigations and human imaging studies have proposed that the augmented dopamine system function observed in schizophrenia patients may be secondary to aberrant hippocampal activity. Thus, we posit that the hippocampus represents a novel therapeutic target for the treatment of schizophrenia. Here we provide evidence of the effectiveness of a unique approach aimed at decreasing hippocampal function in a rodent model of schizophrenia. Specifically, in a rodent model of schizophrenia, we demonstrate that ventral hippocampal (vHipp) deep brain stimulation (DBS) can normalize aberrant dopamine neuron activity and behaviors associated with positive symptoms. In addition, we provide evidence that this approach may also be effective in restoring deficits in cognitive function, often left unaltered by conventional antipsychotic medications. Therefore, we have provided initial preclinical evidence demonstrating the feasibility of hippocampal DBS as a potential novel approach for the treatment of schizophrenia.

Aberrant hippocampal activity is observed in individuals with schizophrenia and is thought to underlie the augmented dopamine system function associated with psychosis. The pathway by which the ventral hippocampus (vHipp) regulates dopamine neuron activity has been demonstrated previously and involves a glutamatergic projection to the nucleus accumbens (NAc). Recent postmortem studies have confirmed glutamatergic abnormalities in the NAc of individuals with schizophrenia. Specifically, an increase in vesicular glutamate transporter 2 (vGlut2) expression was reported. Although projections from the hippocampus do express vGlut2, inputs from the thalamus are more likely to account for this alteration; however, the role of thalamic inputs to the NAc in the regulation of dopamine neuron activity has not been elucidated. Here, using male Sprague Dawley rats, we demonstrate that a subset of NAc medium spiny neurons receive convergent inputs from the vHipp and paraventricular nucleus of the thalamus (PVT), with both regions working synergistically to regulate dopamine neuron activity. Activation of either the vHipp or PVT increases the number of spontaneously active dopamine neurons in the ventral tegmental area. Moreover, this regulation requires simultaneous activity in both regions because PVT inactivation can reverse vHipp-induced increases in dopamine neuron population activity and vHipp inactivation can reverse PVT-induced increases. This is relevant to schizophrenia because inactivation of either the vHipp or PVT is sufficient to reverse aberrant dopamine system function in two distinct rodent models. These data suggest that thalamic abnormalities may contribute to the aberrant dopamine system function observed in schizophrenia and that the PVT represents a novel site of intervention for psychosis.

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.