Deletion of dopamine D ₂ receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes

Abstract

Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis. Here, we show that selective dopamine D receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. Our findings show that dopamine D receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.

High Sucrose Diets Contribute to Brain Angiopathy with Impaired Glucose Uptake, and Psychosis-related Higher Brain Dysfunctions in Mice

“…2). Genetically induced PV-neuron-specific hypo-function leads to an elevated excitation and inhibition ratio in the ventral hippocampus 74 . Recent studies have suggested that chronic stresses also induce hypo-function of interneurons, including PV neurons, and hyperactivity of excitatory neurons in the hippocampus, cortex, and amygdala 75 .…”

“…Recent studies have suggested that chronic stresses also induce hypo-function of interneurons, including PV neurons, and hyperactivity of excitatory neurons in the hippocampus, cortex, and amygdala 75 . Exacerbated pyramidal neuron activity in the ventral hippocampus may underlie the aberrant modulation of DA release from dopaminergic neurons of the midbrain after exposure to an adverse environmental stimulus, such as amphetamine 74,76,77 .…”

“…Moreover, the induction of pan-interneuronal hypo-function (including PV neurons) using the Gad65-Cre-dependent artificial Gai-coupled receptor (hM4Di) expression triggers hyper-locomotion activity without amphetamine stimulation 30 . In addition, aripiprazole exerts its inhibitory effect toward amphetamine-induced hyperactivity partly through the expression of D2 receptors in PV neurons 74 . In line with these results, the PV neuron dysfunction that was induced by excessive sucrose intake in Glo1 heterozygous mice may be a major cause of the DA-dependent hyper-locomotion activity observed in these animals (Figs 1h,i, and 2).…”

Highly Sensitive and Selective Electrochemical Detection of Dopamine using Hybrid Bilayer Membranes

“…Dopamine (DA), a typical neurotransmitter, plays a critical role in the central nervous systems to control reward-related behaviors, movement initiation, release of hormones, etc. [1][2][3] An abnormal level of DA can lead to severe diseases, such as Parkinson's, [4] schizophrenia, [5] and depression. [6] The reliable and accurate detection of DA, however, is not easy.…”

Retrograde labeling illuminates distinct topographical organization of D1 and D2 receptor-positive neurons in the prefrontal cortex of mice

“…Although, these studies elegantly outline the role of sub-regions in the PFC or striatum, few studies have explored the neuronal and molecular diversity of PFC pyramidal neurons involved in regulating motivation and cognition. Dopamine and its receptors in the PFC also regulate motivated behavior and cognitive flexibility (Barker et al, 2013;Goldman-Rakic, 1998;Hitchcott et al, 2007;Natsheh and Shiflett, 2018;Ott and Nieder, 2019) Dopamine activates D1 (stimulatory Gαs-coupled) and D2 (inhibitory Gαi-coupled) class of receptors in the PFC, which modulate the activity of both pyramidal neurons and interneurons (Ferguson and Gao, 2018;Santana et al, 2009;Tomasella et al, 2018;O'Donnell, 2004, 2007). Moreover, pharmacological targeting of D1Rs or D2Rs, or genetic deletion of D2Rs in the PFC can regulate dopamine-dependent behaviors such as locomotion and goal-directed behavior (Barker et al, 2013;Del Arco et al, 2007;Hitchcott et al, 2007;Natsheh and Shiflett, 2018;Tomasella et al, 2018;Urs et al, 2016).…”