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Properties of cannabinoid-dependent long-term depression in the leech

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Abstract

Previously, a cannabinoid-dependent form of long-term depression (LTD) was discovered at the polysynaptic connection between the touch mechanosensory neuron and the S interneuron (Li and Burrell in J Comp Physiol A 195:831–841, 2009). In the present study, the physiological properties of this cannabinoid-dependent LTD were examined. Increases in intracellular calcium in the S interneuron are necessary for this form of LTD in this circuit. Calcium signals contributing to cannabinoid-dependent LTD are mediated by voltage-dependent calcium channel and release of calcium from intracellular stores. Inositol triphosphate receptors, but not ryanodine receptors, appear to mediate this store-released calcium signal. Cannabinoid-dependent LTD also requires activation of metabotropic serotonin receptors, possibly a serotonin type 2-like receptor. Finally, this form of LTD involves the stimulation of nitric oxide synthase and a decrease in cyclic adenosine monophosphate signaling, both of which appeared to be downstream of cannabinoid receptor activation. Based on these findings, the cellular signaling mechanisms of cannabinoid-dependent LTD in the leech are remarkably similar to vertebrate forms of cannabinoid-dependent synaptic plasticity.

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Abbreviations

α-Me-5-HT:

Alpha-methyl-5-hydroxytryptamine

2-AG:

2-Arachidonyl glycerol

AMPA:

α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid

AM251:

1-(2,4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide

ANOVA:

Analysis of variance

AP5:

2-Amino-5-phosphonopentanoic acid

BAPTA:

2-Bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid

Ca2+ :

Calcium

cAMP:

Cyclic adenosine monophosphate

CNS:

Central nervous system

DMSO:

Dimethyl sulfoxide

d-NAME:

NG-nitro-d-arginine methyl ester

EGTA:

Ethylene glycol tetraacetic acid

EPSP:

Excitatory post-synaptic potential

5HT:

5-Hydroxytryptamine (serotonin)

5-HT2 R:

5-Hydroxytryptamine (serotonin) type 2 receptor

IP3 :

Inositol triphosphate

KAc :

Potassium acetate

LFS:

Low frequency stimulation

l-NAME:

NG-nitro-l-arginine methyl ester

LTD:

Long-term depression

LTP:

Long-term potentiation

MCPG:

Methyl-4-carboxyphenylglycine

MK801:

(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine

Ni2+ :

Nickel

NMDAR:

N-methyl-d-aspartic acid receptor

VDCC:

Voltage-dependent Ca2+ channels

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Acknowledgments

The authors thank Drs. Brenda Moss and Kathryn Grey for their helpful comments during the preparation of this manuscript. Supported by grants from the South Dakota Spinal Cord/Traumatic Brain Injury Research Council (BDB) and by a subproject of the National Institutes of Health Center of Biomedical Research Excellence (NIH/COBRE) grant (P20 RR015567).

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Authors and Affiliations

  1. Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine at the University of South Dakota, Vermillion, SD, 57069, USA

    Qin Li & Brian D. Burrell

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  1. Qin Li
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  2. Brian D. Burrell
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Correspondence to Brian D. Burrell.

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Supplemental Figure 1

: LFS (1Hz, 900 s) induced depression in the electrical component of T-to-S synaptic connection and this depression was blocked by EGTA injection into the S cell (one-way ANOVA, F2, 17 = 40.9, P < 0.001, Newman Keuls post-hoc test between EGTA + LFS group and saline LFS group, P <0.001). EGTA treatment without LFS did not alter the electrical EPSP (Post-hoc Newman Keuls test between EGTA + LFS group and EGTA without LFS group, P > 0.05) (EPS 2194 kb)

Supplemental Figure 2

: The role of intracellular and extracellular Ca2+ sources on depression of the electrical EPSP (a) Ni2+ (1 mM) prevented the LTD following LFS (one-way ANOVA of the Ni2+ + LFS and Saline + LFS groups, F1,8 = 29.13, P < 0.001), but did not affect basal synaptic transmission (n = 5 in each group; one-way ANOVA for no LFS groups, F1,8 = 2.74, P > 0.05). (b) Similar to its effect on chemical synaptic transmission, thapsigargin (1 µM) blocked LTD of the electrical EPSP (One-way ANOVA, F2, 12 = 4.63, P < 0.05; post-hoc Newman Keuls test between Thapsigargin + LFS and DMSO + LFS group, P < 0.05). Both TMB-8 (50 µM) and ryanodine (50 µM) also prevented LTD of the electrical synapse (post-hoc Newman Keuls test, Ryanodine + LFS and DMSO + LFS group P < 0.05; TMB-8 + LFS and DMSO + LFS group P < 0.05) (EPS 2303 kb)

Supplemental Figure 3

: The effect of 5-HT and metabotropic glutamate receptor antagonists on depression of the electrical EPSP. Depression was blocked by the 5-HT receptor antagonists methysergide and ritanserin, but not affected by the metabotropic glutamate receptor antagonist MCPG (one-way ANOVA of LFS groups, F3, 18 = 14.83, P < 0.001; post-hoc Newman Keuls test between Saline + LFS and MCPG + LFS groups, P > 0.05; post-hoc Newman Keuls test between Saline + LFS and Methysergide + LFS group, P < 0.001; post-hoc Newman Keuls test between Saline + LFS and Ritanserin + LFS group, P < 0.01) (EPS 2230 kb)

Supplemental Figure 4

: The effect of nitric oxide synthase inhibitor on depression of the electrical EPSP. Both D-NAME and L-NAME bath application had no affect on T-to-S electrical transmission when LFS was omitted. When L-NAME and LFS were combined a partial reduction in LTD of the electrical synapse was observed, but this effect was not statistically significant (one-way ANOVA of the L-NAME + LFS and D-NAME + LFS groups, F1,8 = 1.65, P > 0.05). However, L-NAME did block depression of the electrical EPSP following CP55 940 treatment (one-way ANOVA of the CP55 940 + L-NAME and CP55 940 + D-NAME groups, F1, 6 = 8.30, P < 0.05) (EPS 2206 kb)

Supplemental Figure 5

: The effect of cAMP phosphodiesterase inhibitor on depression of the electrical EPSP. Rolipram (0.1 µM) prevented LTD of the electrical EPSP following LFS (one-way ANOVA of the Rolipram + LFS and DMSO + LFS groups, F1, 8 = 35.12, P < 0.001). Rolipram also blocked LTD of the electrical EPSP following CP55 940 treatment (one-way ANOVA of the CP55 940 and CP55 940 + Rolipram groups, F1, 10 = 7.71, P < 0.05) (EPS 2215 kb)

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Li, Q., Burrell, B.D. Properties of cannabinoid-dependent long-term depression in the leech. J Comp Physiol A 196, 841–851 (2010). https://doi.org/10.1007/s00359-010-0566-9

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