The release of GABA from cholecystokinin-containing interneurons is modulated by type-1 cannabinoid receptors (CB1). Here we tested the hypothesis that the strength of CB1-mediated modulation of GABA release is related to the CB1 content of axon terminals. Basket cell boutons have on average 78% higher CB1 content than those of dendritic-layer-innervating (DLI) cells, a consequence of larger bouton surface and higher CB1 density. The CB1 antagonist AM251 caused a 54% increase in action potential-evoked [Ca2+] in boutons of basket cells, but not in DLI cells. However, the effect of AM251 did not correlate with CB1 immunoreactivity of individual boutons. Moreover, a CB1 agonist decreased [Ca2+] in a cell type- and CB1-content-independent manner. Replica immunogold labelling demonstrated the colocalization of CB1 with the Cav2.2 Ca2+ channel subunit. Our data suggest that only a subpopulation of CB1s, within nanometre distances from their target Cav2.2 channels, are responsible for endocannabinoid-mediated modulation of GABA release.

Tonic endocannabinoid-mediated modulation ofGABA release is independent of the CB1 contentof axon terminals

Lily Bulb and Rehmannia Decoction (LBRD), is a traditional Chinese formula that has been shown to be safe and effective against depression; however, its material basis and pharmacological mechanisms remain unknown. Here, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) and high-performance liquid chromatography (HPLC) were used to identify the chemical spectrum and qualitatively identify the major active ingredients in the LBRD standard decoction, respectively. Subsequently, we assessed the behavior, neuronal function and morphology, neurotransmitter levels, hypothalamic–pituitary–adrenal (HPA)-axis associated hormones, inflammatory cytokine levels, and miRNA/mRNA expression alterations in an in vitro/vivo depression model treated by the LBRD standard decoction. Finally, miRNA/mRNA regulatory networks were created through bioinformatics analysis, followed by functional experiments to verify its role in LBRD standard decoction treatment. A total of 32 prototype compounds were identified in the LBRD standard decoction, and the average quality of verbascoside in the fresh lily bulb decoction, fresh raw Rehmannia juice, and the LBRD standard decoction were 0.001264%, 0.002767%, and 0.009046% (w/w), respectively. Administration of the LBRD standard decoction ameliorated chronic unpredictable mild stress (CUMS)-induced depression-like phenotypes and protected PC12 cells against chronic corticosterone (CORT)-induced injury. The levels of neurotransmitter, cytokine, stress hormones and neuronal morphology were disrupted in the depression model, while LBRD standard decoction could work on these alterations. After LBRD standard decoction administration, four differentially expressed miRNAs, rno-miR-144-3p, rno-miR-495, rno-miR-34c-5p, and rno-miR-24-3p, and six differentially expressed mRNAs, Calml4, Ntrk2, VGAT, Gad1, Nr1d1, and Bdnf overlapped in the in vivo/vitro depression model. Among them, miR-144-3p directly mediated GABA synthesis and release by targeting Gad1 and VGAT, and miR-495 negatively regulated BDNF expression. The LBRD standard decoction can reverse the above miRNA/mRNA network-mediated GABA and BDNF expression in the in vivo/vitro depression model. Collectively, the multi-components of the LBRD standard decoction altered a series of miRNAs in depression through mediating GABAergic synapse, circadian rhythm, and neurotrophic signaling pathway etc., thereby abolishing inhibitory/excitatory neurotransmitter deficits, recovering the pro-/anti-inflammatory cytokine levels and regulating the HPA-axis hormone secretion to achieve balance of the physiological function of the whole body.

/pdf/integrated-analysis-of-the-chemical-material-basis-and-2vnlhf4qff.pdf

Integrated analysis of the chemical-material basis and molecular mechanisms for the classic herbal formula of Lily Bulb and Rehmannia Decoction in alleviating depression

Baihe Dihuang (Lilium Henryi Baker and Rehmannia Glutinosa) decoction attenuates somatostatin interneurons deficits in prefrontal cortex of depression via miRNA-144-3p mediated GABA synthesis and release.

Altered neurotransmission in stress-induced depressive disorders: The underlying role of the amygdala in depression

Activation of nociceptin opioid peptide receptors (NOP, a.k.a. opioid-like receptor-1, ORL-1) by the ligand nociceptin/orphanin FQ, leads to G protein-dependent regulation of Cav2.2 (N-type) voltage-gated calcium channels (VGCCs). This typically causes a reduction in calcium currents, triggering changes in presynaptic calcium levels and thus neurotransmission. Because of the widespread expression patterns of NOP and VGCCs across multiple brain regions, the dorsal horn of the spinal cord, and the dorsal root ganglia, this results in the alteration of numerous neurophysiological features. Here we review the regulation of N-type calcium channels by the NOP-nociceptin system in the context of neurological conditions such as anxiety, addiction, and pain. 

/pdf/regulation-of-n-type-calcium-channels-by-nociceptin-14dx3otc.pdf

Regulation of N-type calcium channels by nociceptin receptors and its possible role in neurological disorders

Presynaptic N-type (CaV2.2) calcium channels are key for action potential evoked transmitter release in the peripheral and central nervous system. Previous studies have highlighted the functional relevance of N-type calcium channels at both the peripheral and central level. In the periphery, the N-type calcium channels regulate nociceptive and sympathetic responses. At the central level, N-type calcium channels have been linked to aggression, hyperlocomotion, and anxiety. Among the areas of the brain that are involved in anxiety are the basolateral amygdala, medial prefrontal cortex, and ventral hippocampus. These three areas share similar characteristics in their neuronal circuitry. Pyramidal projection neurons are under the inhibitory control of a wide array of interneurons including those that express the peptide cholecystokinin. This type of interneuron is well-known to rely on N-type calcium channels to release GABA in the hippocampus, however whether these channels control GABA release from cholecystokinin-expressing interneurons in the basolateral amygdala and medial prefrontal cortex is not known. Here using sophisticated mouse models to genetically label cholecystokinin-expressing interneurons, we found that N-type calcium channels control ~50% of GABA release in basolateral amygdala. By contrast, N-type calcium channels are functionally absent in synapses of cholecystokinin-expressing interneurons of medial prefrontal cortex. Our findings provide insights into the precise localization of N-type calcium channels in synapses of brain areas related to anxiety.

/pdf/n-type-calcium-channels-control-gabaergic-transmission-in-vcd6fm2vdy.pdf

N-type calcium channels control GABAergic transmission in brain areas related to fear and anxiety

N-type (CaV2.2) calcium channels are key for action potential-evoked transmitter release in the peripheral and central nervous system. Previous studies have highlighted the functional relevance of N-type calcium channels at both the peripheral and central level. In the periphery, N-type calcium channels regulate nociceptive and sympathetic responses. At the central level, N-type calcium channels have been linked to aggression, hyperlocomotion, and anxiety. Among the areas of the brain that are involved in anxiety are the basolateral amygdala, medial prefrontal cortex, and ventral hippocampus. These three areas share similar characteristics in their neuronal circuitry, where pyramidal projection neurons are under the inhibitory control of a wide array of interneurons including those that express the peptide cholecystokinin. This type of interneuron is well-known to rely on N-type calcium channels to release GABA in the hippocampus, however, whether these channels control GABA release from cholecystokinin-expressing interneurons in the basolateral amygdala and medial prefrontal cortex is not known. Here, using mouse models to genetically label cholecystokinin-expressing interneurons and electrophysiology, we found that in the basolateral amygdala, N-type calcium channels control ~50% of GABA release from these neurons onto pyramidal cells. By contrast, in the medial prefrontal cortex N-type calcium channels are functionally absent in synapses of cholecystokinin-expressing interneurons, but control ~40% of GABA release from other types of interneurons. Our findings provide insights into the precise localization of N-type calcium channels in interneurons of brain areas related to anxiety.

/pdf/n-type-calcium-channels-control-gabaergic-transmission-in-3q6ixa5jit.pdf

N-Type Calcium Channels Control GABAergic Transmission in Brain Areas related to Fear and Anxiety

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N-type calcium channels control GABAergic transmission in brain areas related to fear and anxiety

N-Type Calcium Channels Control GABAergic Transmission in Brain Areas related to Fear and Anxiety