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![Pathogenic effects of the D2R antagonist haloperidol on social deficits
a Illustration showing the facilitatory effect of the D2R antagonist haloperidol (Halo) on DA transmission by targeting presynaptic D2Rs. b Schematic and representative traces showing increased DA release (evoked by a burst of electric stimulation [Estim, 50 pulses at 80 Hz] at the medial forebrain bundle) in the mPFC in vivo following i.p. application of Halo (0.4 mg/kg) in juvenile C57 mice. Data from 3 mice. c Representative trace and statistics of spontaneous APs of cortical neurons in mPFC slices in response to DA application (Data are presented as mean ± SEM). Data from 4 mice. d Left, illustration showing the dual effects of Halo on DA transmission by targeting presynaptic and postsynaptic D2Rs. Middle and right, representative traces and statistics of spontaneous APs of mPFC cortical neurons in response to Halo application. Data from 3 mice. e Schematic of bilateral cannula application of Halo into the VTA and the experimental procedure. f-h Representative heat maps and statistics of three-chamber social interaction time in juvenile (6–8 weeks) C57 mice following local application of Halo vs saline control in the VTA. i-k Representative heat maps and statistics of the social novelty test in Halo- vs saline-treated juvenile C57 mice. l Statistics of investigation time in juvenile C57 mice following local application of Halo vs saline control in the VTA in the home-cage social test. Data are shown as box-and-whisker plots, with the median represented by the central line inside each box, the 25th and 75th percentiles represented by the edges of the box, and the whiskers extending to the most extreme data points. Ordinary two-way ANOVA followed by Bonferroni’s post-hoc test for (g,j), two-tailed paired Student’s t-test for (c), or two-tailed Mann-Whitney test for (h,k,l), *P < 0.05, **P < 0.01, ***P < 0.001, n.s. no significant difference. Source data are provided as a Source Data file.](publication/386435800/figure/fig6/AS:11431281295066456@1733393994180/Pathogenic-effects-of-the-D2R-antagonist-haloperidol-on-social-deficits-a-Illustration.png)
Pathogenic effects of the D2R antagonist haloperidol on social deficits a Illustration showing the facilitatory effect of the D2R antagonist haloperidol (Halo) on DA transmission by targeting presynaptic D2Rs. b Schematic and representative traces showing increased DA release (evoked by a burst of electric stimulation [Estim, 50 pulses at 80 Hz] at the medial forebrain bundle) in the mPFC in vivo following i.p. application of Halo (0.4 mg/kg) in juvenile C57 mice. Data from 3 mice. c Representative trace and statistics of spontaneous APs of cortical neurons in mPFC slices in response to DA application (Data are presented as mean ± SEM). Data from 4 mice. d Left, illustration showing the dual effects of Halo on DA transmission by targeting presynaptic and postsynaptic D2Rs. Middle and right, representative traces and statistics of spontaneous APs of mPFC cortical neurons in response to Halo application. Data from 3 mice. e Schematic of bilateral cannula application of Halo into the VTA and the experimental procedure. f-h Representative heat maps and statistics of three-chamber social interaction time in juvenile (6–8 weeks) C57 mice following local application of Halo vs saline control in the VTA. i-k Representative heat maps and statistics of the social novelty test in Halo- vs saline-treated juvenile C57 mice. l Statistics of investigation time in juvenile C57 mice following local application of Halo vs saline control in the VTA in the home-cage social test. Data are shown as box-and-whisker plots, with the median represented by the central line inside each box, the 25th and 75th percentiles represented by the edges of the box, and the whiskers extending to the most extreme data points. Ordinary two-way ANOVA followed by Bonferroni’s post-hoc test for (g,j), two-tailed paired Student’s t-test for (c), or two-tailed Mann-Whitney test for (h,k,l), *P < 0.05, **P < 0.01, ***P < 0.001, n.s. no significant difference. Source data are provided as a Source Data file.
Source publication
Schizophrenia is a severe neuropsychiatric disease, but the initiation mechanisms are unclear. Although antipsychotics are effective against positive symptoms, therapeutic interventions for negative symptoms are limited due to the lack of pathophysiological mechanisms. Here we identify synaptotagmin-11 (Syt11) as a potential genetic risk factor and...
Citations
... In addition to PD, functional abnormalities of DA neurons affect various neurological diseases. Dysfunction of DA neurons in the nigrostriatal pathway will lead to abnormal motor behaviours and cognitive function, which may be associated with neurological disorders, such as Huntington's disease (HD) and schizophrenia [40][41][42][43]. Impaired oxytocin signalling in DA neurons could alter behavioural responses to social novelty and cause autism spectrum disorders [44]. ...
Human midbrain organoids with functional dopaminergic (DA) neurons are invaluable for the therapeutic development of Parkinson's disease (PD). However, current methods face significant limitations, including challenges in generating pint‐sized organoids enriched with DA neurons and the lack of robust functional assays for efficiently evaluating neural networks over extended periods. Here we present an innovative approach that combines developmental patterning with mechanical cutting to produce small midbrain organoids, with diameters less than 300 μm, suitable for long‐term evaluation, along with a comprehensive functional assay system consisting of calcium transient assay, neurite extension assay, and multielectrode array (MEA) assay. Radial cutting of organoids into four to eight portions according to their sizes at the appropriate developmental stage significantly increases the yield of viable organoids while reducing necrotic cell regions. Using the functional assay system, we demonstrate that DA neurons within the organoids extend long projections, respond to dopamine stimulation, and form neural networks characterised by giant depolarising potential‐like events. Our approach supports the generation of midbrain organoids and PD models that can be used for long‐term functional testing.
Dopamine (DA) in the striatum is vital for motor and cognitive behaviors. Midbrain dopaminergic neurons generate both tonic and phasic action potential (AP) firing patterns in behavior mice. Besides AP numbers, whether and how different AP firing patterns per se modulate DA release remain largely unknown. Here by using in vivo and ex vivo models, it is shown that the AP frequency per se modulates DA release through the D2 receptor (D2R), which contributes up to 50% of total DA release. D2R has a voltage‐sensing site at D131 and can be deactivated in a frequency‐dependent manner by membrane depolarization. This voltage‐dependent D2R inhibition of DA release is mediated via the facilitation of voltage‐gated Ca²⁺ channels (VGCCs). Collectively, this work establishes a novel mechanism that APs per se modulate DA overflow by disinhibiting the voltage‐sensitive autoreceptor D2R and thus the facilitation of VGCCs, providing a pivotal pathway and insight into mammalian DA‐dependent functions in vivo.
