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Developmental Changes in Serotonergic Modulation of GABAergic Synaptic Transmission and Postsynaptic GABAA Receptor Composition in the Cerebellar Nuclei

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Abstract

Outputs from the cerebellar nuclei (CN) are important for generating and controlling movement. The activity of CN neurons is controlled not only by excitatory inputs from mossy and climbing fibers and by γ-aminobutyric acid (GABA)-based inhibitory transmission from Purkinje cells in the cerebellar cortex but is also modulated by inputs from other brain regions, including serotonergic fibers that originate in the dorsal raphe nuclei. We examined the modulatory effects of serotonin (5-HT) on GABAergic synapses during development, using rat cerebellar slices. As previously reported, 5-HT presynaptically decreased the amplitudes of stimulation-evoked inhibitory postsynaptic currents (IPSCs) in CN neurons, with this effect being stronger in slices from younger animals (postnatal days [P] 11–13) than in slices from older animals (P19–21). GABA release probabilities accordingly exhibited significant decreases from P11–13 to P19–21. Although there was a strong correlation between the GABA release probability and the magnitude of 5-HT-induced inhibition, manipulating the release probability by changing extracellular Ca2+ concentrations failed to control the extent of 5-HT-induced inhibition. We also found that the IPSCs exhibited slower kinetics at P11–13 than at P19–21. Pharmacological and molecular biological tests revealed that IPSC kinetics were largely determined by the prevalence of α1 subunits within GABAA receptors. In summary, pre- and postsynaptic developmental changes in serotonergic modulation and GABAergic synaptic transmission occur during the second to third postnatal weeks and may significantly contribute to the formation of normal adult cerebellar function.

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Abbreviations

5-HT:

Serotonin

ACSF:

Artificial cerebrospinal fluid

ATP:

Adenosine triphosphate

CNQX:

6-Cyano-7-nitroquinoxaline-2,3-dione

D-APV:

D-2-Amino-5-phosphonopentanoic acid

CN:

Cerebellar nuclei

eIPSC:

Evoked IPSC

IPSC:

Inhibitory postsynaptic current

GABA:

γ-Aminobutyric acid

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GTP:

Guanosine triphosphate

K-EGTA:

Egtazic acid potassium salt

mIPSC:

Miniature IPSC

OCD:

Obsessive-convulsive disorder

mRNA:

Messenger RNA

P#:

Postnatal day #

PC:

Purkinje cell

PPR:

Paired pulse ratio

TBST:

Tris-buffered saline-Tween 20

TPMPA:

(1,2,5,6-Tetrahydropyridin-4-yl) methylphosphinic acid

VGCC:

Voltage-gated calcium channel

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Acknowledgements

We thank Dr. K Kobayashi of Nippon Medical School for valuable discussions.

Funding

This work was supported by a Grant-in-Aid for Scientific Research (grant number 19500279) from the Japanese Ministry of Education, Science, Sports and Culture.

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  1. Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan

    Fumihito Saitow, Masatoshi Nagano & Hidenori Suzuki

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  1. Fumihito Saitow
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  2. Masatoshi Nagano
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Correspondence to Fumihito Saitow.

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Saitow, F., Nagano, M. & Suzuki, H. Developmental Changes in Serotonergic Modulation of GABAergic Synaptic Transmission and Postsynaptic GABAA Receptor Composition in the Cerebellar Nuclei. Cerebellum 17, 346–358 (2018). https://doi.org/10.1007/s12311-018-0922-9

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