Blockade of Dopamine D2/3 Receptors Improves Neuronal Network Oscillations in Heterozygous Reeler Mice

Schizophrenia (SCZ) is a severe mental illness characterized by polygenic abnormalities, neural network dysfunction, and cognitive impairment. Mice with reelin gene deficiency (heterozygous reeler mice, HRM) exhibit social withdrawal and dysregulated neurotransmitter systems, including dopamine (DA), similar to abnormalities observed in SCZ patients; therefore, HRM are regarded as a relevant animal model of SCZ. Neural network oscillations in the gamma frequency band (30-100 Hz; γ oscillations) play a crucial role in information processing and neural synchronization in the brain, and disrupted γ oscillations are a hallmark of SCZ. Our previous work showed dysregulated DA modulation of hippocampal γ oscillations in HRM, although the underlying mechanisms remained unclear. In this study, we examined the effects of various DA receptor (DR) agonists and antagonists on hippocampal γ oscillations in wild-type (WT) and HRM to identify mechanisms that may restore DA-dependent modulation of neural network activity in HRM.

Behavioral performance was assessed using the elevated plus maze (EPM), open field test (OFT), Morris water maze (MWM), and three-chamber social interaction test. Local field potential (LFP) recordings were used to monitor hippocampal CA3 γ oscillations. Western blotting was performed to quantify expression levels of DA receptor subunits.

Behavioral tests revealed that HRM displayed reduced social interaction and impaired social novelty preference (three-chamber test), fewer entries and reduced time spent in the open arms (EPM), while maintaining normal motor activity (OFT) and learning and memory abilities (MWM). These findings suggest that HRM exhibit anxiety-like behaviors and deficits in social interaction. LFP recordings showed that the D1R agonist (SKF-81297) and D2R agonist (Quinpirole) increased γ-oscillation power (γ power) in WT mice but had no effect in HRM. The D3R agonist (PD- 128907) did not alter γ power in either genotype. The D4R agonist (PD-168077) caused a modest increase in γ power in HRM. Notably, the D3R antagonist (GR103691) and the D2R antagonist (Phenothiazine), but not the D1R antagonist (SKF-83566) or the D4R antagonist (L-745870), significantly enhanced γ power in HRM. Western blot analysis revealed upregulated D3R expression in the hippocampus of HRM, while D1R, D2R, and D4R levels remained comparable to WT.

HRM exhibits disrupted dopaminergic modulation of γ oscillations, likely due to impaired D1R/D2R signaling combined with elevated D3R expression. Pharmacological blockade of D3R and, to some extent, D2R effectively restores γ-oscillation modulation in HRM, highlighting the critical role of these receptors in SCZ-related network dysfunction.

Our findings demonstrate that selective blockade of D2/3 receptors restores DAdependent neuronal network synchronization in HRM. This mechanism may underlie the therapeutic efficacy of D2/3 antagonists in the treatment of schizophrenia.