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Syt11 cKO and DA over-transmission lead to long-lasting structural and functional alterations in the mPFC a, b Representative micrographs and statistics of MAP2-positive neurons in the mPFC of adult Syt11-cKO (n = 6) vs control (n = 5) mice. Scale bars: 50 μm for left, 20 μm for right. c, d Representative micrographs and statistics of TH-positive neurites in the mPFC of adult Syt11-cKO (n = 6) vs control (n = 5) mice. e Representative sEPSC traces and statistics of the amplitude and frequency of sEPSC in mPFC cortical neurons from adult Syt11-cKO (n = 6) vs control (n = 6) mice. f Representative mEPSC traces and statistics of the amplitude and frequency of mEPSC in mPFC cortical neurons of adult Syt11-cKO (n = 6) vs control (n = 6) mice. g Left, schematic of virus injection (TH-Cre-EGFP/TH-EGFP) into the VTA of neonatal Syt11-flox/flox mice (P0) for the generation of Syt11 P0-cKO or control mice. Middle and right, representative AP traces and statistics of spontaneous AP firing rates in mPFC cortical neurons of adult (3 months) Syt11 P0-cKO (n = 4) vs control (n = 3) mice. h Left, schematic showing the co-injection of TH-Cre and DIO-hM3Dq-mCherry/DIO-mCherry viruses into the VTA of neonatal C57 mice (hM3D, P0) and the experimental procedure. Middle and right, representative AP traces and statistics of spontaneous AP frequency in mPFC cortical neurons of adult repetitive CNO-treated hM3Dq-expressing (n = 5) vs control (n = 4) mice. i The heatmap showing gene expression profiling determined by genome-wide RNA sequencing (RNA-Seq) of the mPFC in Syt11 cKO (n = 4) vs control (n = 3) mice. Rows represent differentially expressed genes (DEGs), and columns represent transcriptomic profiles of individual animals. j Volcano plots showing gene expression profiling of the mPFC in Syt11 cKO vs control mice. The x-axis represents log2 fold change (FC) between the two groups. k Ingenuity gene ontology (GO) analysis indicating significantly enriched GO terms in cellular components and biological processes. 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. Two-tailed Mann-Whitney test, *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
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.