scholarly journals GABAB Receptors Augment TRPC3-Mediated Slow Excitatory Postsynaptic Current to Regulate Cerebellar Purkinje Neuron Response to Type-1 Metabotropic Glutamate Receptor Activation

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 90 ◽  
Author(s):  
Jinbin Tian ◽  
Michael Zhu

During strong parallel fiber stimulation, glutamate released at parallel fiber-Purkinje cell synapses activates type-1 metabotropic glutamate receptor (mGluR1) to trigger a slow excitatory postsynaptic current (sEPSC) in cerebellar Purkinje neurons. The sEPSC is mediated by transient receptor potential canonical 3 (TRPC3) channels. Often co-localized with mGluR1 in Purkinje neuron dendrites are type B γ-aminobutyric acid receptors (GABABRs) that respond to inhibitory synaptic inputs from interneurons located in the molecular layer of cerebellar cortex. It has been shown that activation of postsynaptic GABABRs potentiates mGluR1 activation-evoked sEPSC in Purkinje cells, but the underlying molecular mechanism remains elusive. Here we report that the augmentation of mGluR1-sEPSC by GABABR activation in Purkinje neurons is completely absent in TRPC3 knockout mice, but totally intact in TRPC1-, TRPC4-, and TRPC1,4,5,6-knockout mice, suggesting that TRPC3 is the only TRPC isoform that mediates the potentiation. Moreover, our results indicate that the potentiation reflects a postsynaptic mechanism that requires both GABABRs and mGluR1 because it is unaffected by blocking neurotransmission with tetrodotoxin but blocked by inhibiting either GABABRs or mGluR1. Furthermore, we show that the co-stimulation of GABABRs has an effect on shaping the response of Purkinje cell firing to mGluR1-sEPSC, revealing a new function of inhibitory input on excitatory neurotransmission. We conclude that postsynaptic GABABRs regulate Purkinje cell responses to strong glutamatergic stimulation through modulation of mGluR1-TRPC3 coupling. Since mGluR1-TRPC3 coupling is essential in cerebellar long-term depression, synapse elimination, and motor coordination, our findings may have implications in essential cerebellar functions, such as motor coordination and learning.

1997 ◽  
Vol 78 (1) ◽  
pp. 63-75 ◽  
Author(s):  
Jeffrey G. Netzeband ◽  
Kathy L. Parsons ◽  
Dan D. Sweeney ◽  
Donna L. Gruol

Netzeband, Jeffrey G., Kathy L. Parsons, Dan D. Sweeney, and Donna L. Gruol. Metabotropic glutamate receptor agonists alter neuronal excitability and Ca2+ levels via the phospholipase C transduction pathway in cultured Purkinje neurons. J. Neurophysiol. 78: 63–75, 1997. Selective agonists for metabotropic glutamate receptor (mGluR) subtypes were tested on mature, cultured rat cerebellar Purkinje neurons (≥21 days in vitro) to identify functionally relevant mGluRs expressed by these neurons and to investigate the transduction pathways associated with mGluR-mediated changes in membrane excitability. Current-clamp recordings (nystatin/perforated-patch method) were used to measure the membrane response of Purkinje neurons to brief microperfusion pulses (1.5 s) of the group I (mGluR1/mGluR5) agonists (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid (300 μM), quisqualate (5 μM), and ( R,S)-3,5-dihydroxyphenylglycine (50–500 μM). All group I mGluR agonists elicited biphasic membrane responses and burst activity in the Purkinje neurons. In addition, the group I mGluR agonists produced alterations in the active membrane properties of the Purkinje neurons and depressed the off response after hyperpolarizing current injection. In parallel microscopic Ca2+ imaging experiments, application of the group I mGluR agonists to fura-2-loaded cells elicited increases in intracellular Ca2+ in both the somatic and dendritic regions. The group II (mGluR2/mGluR3) agonist (2 S,3 S,4 S)-α-(carboxycyclopropyl)-glycine (10 μM) and the group III (mGluR4/mGluR6/mGluR7/mGluR8) agonists l(+)-2-amino-4-phosphonobutyric acid (1 mM) and O-phospho-l-serine (200 μM) had no effect on the membrane potential or intracellular Ca2+ levels of the Purkinje neurons. The cultured Purkinje neurons, but not granule neurons or interneurons, showed immunostaining for mGluR1α in both the somatic and dendritic regions. All effects of the group I mGluR agonists were blocked by (+)-α-methyl-4-carboxyphenylglycine (1 mM), an mGluR antagonist. Furthermore, the phospholipase C inhibitor 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (2 μM) blocked the group I mGluR agonist-mediated electrophysiological response and greatly attenuated the Ca2+ signal elicited by group I mGluR agonists, particularly in the dendrites. The inactive analogue1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]2,5-pyrrolidine-dione (2 μM) was relatively ineffective against the electrophysiological response and Ca2+ signal. These results indicate that functional group I mGluRs (but not group II or III mGluRs) can be activated on mature Purkinje neurons in culture and result in changes in neuronal excitability and intracellular Ca2+ mediated through phospholipase C. These data obtained from a defined neuronal type, the Purkinje neuron, confirm biochemical and molecular studies on the transduction mechanisms of group I mGluRs and show that this transduction pathway is linked to neuronal excitability and intracellular Ca2+ release in the Purkinje neurons.


2010 ◽  
Vol 37 (5) ◽  
pp. 615-624 ◽  
Author(s):  
Kazuhiko Yanamoto ◽  
Fujiko Konno ◽  
Chika Odawara ◽  
Tomoteru Yamasaki ◽  
Kazunori Kawamura ◽  
...  

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