Abstract
Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorised users.Schizophrenia is a severe mental disorder and a significant global health burden, highlighting the need to better understand its neurobiology in order to develop improvedReproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a. . .treatments [1]
Sub-chronic ketamine treatment significantly increased striatal dopamine synthesis capacity compared to controls, with an effect size of d = 2.5 (P < 0.001, t13 = 4.74) (Fig. 1b, c, Supplementary Table 1)
Repeated ketamine administration induced locomotor sensitization, an effect that was sustained following 2-day washout of ketamine (Fig. 1d–f; Supplementary Fig. 1). These findings indicate that sub-chronic ketamine administration induces both an increase in dopamine synthesis capacity and behavioural changes relevant to schizophrenia
Summary
Increased dopamine synthesis capacity is associated with both the development of psychosis [10] and the severity of symptoms [11]. It has been suggested that impaired PV neuronal function in the cortex and hippocampus may lead to disinhibition of mesostriatal dopamine neuron activity via a polysynaptic pathway [19]. It is not clear if it is possible to develop a pre-clinical model of the increased dopamine synthesis capacity seen in patients using an NMDAR antagonist, and whether it is possible to reverse this by targeting PV-expressing interneurons or other mechanisms
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