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Cannabinoid CB1 receptor signaling dichotomously modulates inhibitory and excitatory synaptic transmission in rat inner retina

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Abstract

In the inner retina, ganglion cells (RGCs) integrate and process excitatory signal from bipolar cells (BCs) and inhibitory signal from amacrine cells (ACs). Using multiple labeling immunohistochemistry, we first revealed the expression of the cannabinoid CB1 receptor (CB1R) at the terminals of ACs and BCs in rat retina. By patch-clamp techniques, we then showed how the activation of this receptor dichotomously regulated miniature inhibitory postsynaptic currents (mIPSCs), mediated by GABAA receptors and glycine receptors, and miniature excitatory postsynaptic currents (mEPSCs), mediated by AMPA receptors, of RGCs in rat retinal slices. WIN55212-2 (WIN), a CB1R agonist, reduced the mIPSC frequency due to an inhibition of L-type Ca2+ channels no matter whether AMPA receptors were blocked. In contrast, WIN reduced the mEPSC frequency by suppressing T-type Ca2+ channels only when inhibitory inputs to RGCs were present, which could be in part due to less T-type Ca2+ channels of cone BCs, presynaptic to RGCs, being in an inactivation state under such condition. This unique feature of CB1R-mediated retrograde regulation provides a novel mechanism for modulating excitatory synaptic transmission in the inner retina. Moreover, depolarization of RGCs suppressed mIPSCs of these cells, an effect that was eliminated by the CB1R antagonist SR141716, suggesting that endocannabinoid is indeed released from RGCs.

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Abbreviations

ACs:

Amacrine cells

AMPARs:

AMPA receptors

2-AG:

2-Arachidonoylglycerol

Anandamide, AEA:

N-Arachidonoylethanolamine

ACSF:

Artificial cerebral spinal fluid

BCs:

Bipolar cells

CB1R:

CB1 receptor

CNS:

Central nervous system

eCB:

Endocannabinoid

eIPSCs:

Evoked inhibitory postsynaptic currents

([Ca2+]o):

Extracellular calcium concentration

FAAH:

Fatty acid amide hydrolase

GABAARs:

GABAA receptors

GlyRs:

Glycine receptors

INL:

Inner nuclear layer

IPL:

Inner plexiform layer

([Ca2+]i):

Intracellular Ca2+ concentration

MIB:

Mibefradil

mIPSCs:

Miniature inhibitory postsynaptic currents

mEPSCs:

Miniature excitatory postsynaptic currents

NIM:

Nimodipine

PPR:

Paired-pulse ratio

PB:

Phosphate buffer

PBS:

Phosphate buffer saline

PFA:

Paraformaldehyde

RGCs:

Retinal ganglion cells

SR:

SR141716

WIN:

WIN 55212-2

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Acknowledgments

This work was supported by grants from the National Program of Basic Research sponsored by the Ministry of Science and Technology of China (2013CB835100; 2011CB504602), the National Natural Science Foundation of China (31271173; 31470054), the Key Research Program of Science and Technology Commissions of Shanghai Municipality (11JC1401200; 13DJ1400302).

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The authors declare that they have no competing interests.

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The authors declare that the manuscript does not contain clinical studies or patient data.

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  1. Institutes of Brain Science, Institute of Neurobiology, State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan Rd, Shanghai, 200032, China

    Xiao-Han Wang, Yi Wu, Xiao-Fang Yang, Yanying Miao, Chuan-Qiang Zhang, Ling-Dan Dong, Xiong-Li Yang & Zhongfeng Wang

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  1. Xiao-Han Wang
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  2. Yi Wu
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Correspondence to Zhongfeng Wang.

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X.-H. Wang and Y. Wu contributed equally to this work.

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Wang, XH., Wu, Y., Yang, XF. et al. Cannabinoid CB1 receptor signaling dichotomously modulates inhibitory and excitatory synaptic transmission in rat inner retina. Brain Struct Funct 221, 301–316 (2016). https://doi.org/10.1007/s00429-014-0908-4

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