Motor cortex can directly drive the globus pallidus neurons in a projection neuron type- dependent manner in the rat
The basal ganglia are critical for the control of motor behaviors and for reinforcement learning. Here, we demonstrate in rats that primary and secondary motor areas (M1 and M2) make functional synaptic connections in the globus pallidus (GP), not usually thought of as an input site of the basal ganglia. Morphological observation revealed that the density of axonal boutons from motor cortices in the GP was 47% and 78% of that in the subthalamic nucleus (STN) from M1 and M2, respectively. Cortical excitation of GP neurons was comparable to that of STN neurons in slice preparations. FoxP2-expressing arkypallidal neurons were preferentially innervated by the motor cortex. The connection probability of cortico-pallidal innervation was higher for M2 than M1. These results suggest that cortico-pallidal innervation is an additional excitatory input to the basal ganglia, and that it can affect behaviors via the cortex-basal ganglia-thalamus motor loop.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files in a Microsoft Exel format are provided for Table 2, for Figures 2C, 2D, 2E, 4A2, 4B2, 4B3, 4B4, 4C, 5B, 5C, 5D, 5F, 6A, 6B, 6C, 6D, and also for Figure 1-Figure supplement 2E, and Figure 2-Figure supplement 1D.
Article and author information
Japan Society for the Promotion of Science London (Grant-in-Aid for Scientific Research(S) 26350983)
- Fuyuki Karube
Japan Society for the Promotion of Science London (Grant-in-Aid for Scientific Research(S) 16H01622)
- Fuyuki Karube
Japan Society for the Promotion of Science London (Grant-in-Aid for Specially Promoted Research 16H06543)
- Susumu Takahashi
Japan Society for the Promotion of Science London (Grant-in-Aid for Scientific Research(S) 16H02840)
- Susumu Takahashi
Japan Society for the Promotion of Science London (Grant-in-Aid for Scientific Research(S) 25282247)
- Fumino Fujiyama
Japan Society for the Promotion of Science London (Grant-in-Aid for Scientific Research(S) 15K12770)
- Fumino Fujiyama
Japan Society for the Promotion of Science London (Scientific Researches on Innovative Areas 26112001)
- Fumino Fujiyama
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal experiments were approved and performed in accordance with the guidelines for the care and use of laboratory animals established by the Committee for Animal Care (Permit Number: A16008, A17001, A18001, A19036) and Use and the Committee for Recombinant DNA Study (Permit Number: D16008, D17001, D18001, D19036) of Doshisha University. All efforts were made to minimize animal suffering and the number of animals used.
- Naoshige Uchida, Harvard University, United States
- Received: June 20, 2019
- Accepted: October 29, 2019
- Accepted Manuscript published: November 12, 2019 (version 1)
- Version of Record published: November 19, 2019 (version 2)
© 2019, Karube et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
- Page views
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Activation of voltage-gated calcium channels at presynaptic terminals leads to local increases in calcium and the fusion of synaptic vesicles containing neurotransmitter. Presynaptic output is a function of the density of calcium channels, the dynamic properties of the channel, the distance to docked vesicles, and the release probability at the docking site. We demonstrate that at Caenorhabditis elegans neuromuscular junctions two different classes of voltage-gated calcium channels, CaV2 and CaV1, mediate the release of distinct pools of synaptic vesicles. CaV2 channels are concentrated in densely packed clusters ~250 nm in diameter with the active zone proteins Neurexin, α-Liprin, SYDE, ELKS/CAST, RIM-BP, α-Catulin, and MAGI1. CaV2 channels are colocalized with the priming protein UNC-13L and mediate the fusion of vesicles docked within 33 nm of the dense projection. CaV2 activity is amplified by ryanodine receptor release of calcium from internal stores, triggering fusion up to 165 nm from the dense projection. By contrast, CaV1 channels are dispersed in the synaptic varicosity, and are colocalized with UNC-13S. CaV1 and ryanodine receptors are separated by just 40 nm, and vesicle fusion mediated by CaV1 is completely dependent on the ryanodine receptor. Distinct synaptic vesicle pools, released by different calcium channels, could be used to tune the speed, voltage-dependence, and quantal content of neurotransmitter release.
- Cell Biology
Caenorhabditis elegans neurons under stress can produce giant vesicles, several microns in diameter, called exophers. Current models suggest that exophers are neuroprotective, providing a mechanism for stressed neurons to eject toxic protein aggregates and organelles. However, little is known of the fate of the exopher once it leaves the neuron. We found that exophers produced by mechanosensory neurons in C. elegans are engulfed by surrounding hypodermal skin cells and are then broken up into numerous smaller vesicles that acquire hypodermal phagosome maturation markers, with vesicular contents gradually degraded by hypodermal lysosomes. Consistent with the hypodermis acting as an exopher phagocyte, we found that exopher removal requires hypodermal actin and Arp2/3, and the hypodermal plasma membrane adjacent to newly formed exophers accumulates dynamic F-actin during budding. Efficient fission of engulfed exopher-phagosomes to produce smaller vesicles and degrade their contents requires phagosome maturation factors SAND-1/Mon1, GTPase RAB-35, the CNT-1 ARF-GAP, and microtubule motor-associated GTPase ARL-8, suggesting a close coupling of phagosome fission and phagosome maturation. Lysosome activity was required to degrade exopher contents in the hypodermis but not for exopher-phagosome resolution into smaller vesicles. Importantly, we found that GTPase ARF-6 and effector SEC-10/exocyst activity in the hypodermis, along with the CED-1 phagocytic receptor, is required for efficient production of exophers by the neuron. Our results indicate that the neuron requires specific interaction with the phagocyte for an efficient exopher response, a mechanistic feature potentially conserved with mammalian exophergenesis, and similar to neuronal pruning by phagocytic glia that influences neurodegenerative disease.