Axon terminal hypertrophy of striatal projection neurons with levodopa-induced dyskinesia priming

Takashi Nakamura; Haruo Nishijima; Fumiaki Mori; Iku Kinoshita; Tomoya Kon; Chieko Suzuki; Koichi Wakabayashi; Masahiko Tomiyama

doi:10.3389/fnins.2023.1169336

Axon terminal hypertrophy of striatal projection neurons with levodopa-induced dyskinesia priming

Front Neurosci. 2023 Jun 7:17:1169336. doi: 10.3389/fnins.2023.1169336. eCollection 2023.

Authors

Takashi Nakamura¹, Haruo Nishijima¹, Fumiaki Mori², Iku Kinoshita¹, Tomoya Kon¹, Chieko Suzuki¹, Koichi Wakabayashi², Masahiko Tomiyama¹

Affiliations

¹ Department of Neurology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
² Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Abstract

Background: A rat model of levodopa-induced dyskinesia (LID) showed enlarged axon terminals of striatal direct pathway neurons in the internal segment of the globus pallidus (GPi) with excessive gamma-aminobutyric acid (GABA) storage in them. Massive GABA release to GPi upon levodopa administration determines the emergence of LID.

Objectives: We examined whether LID and axon terminal hypertrophy gradually develop with repeated levodopa treatment in Parkinsonian rats to examine if the hypertrophy reflects dyskinesia priming.

Methods: 6-hydroxydopamine-lesioned hemiparkinsonian rats were randomly allocated to receive saline injections (placebo group, 14 days; n = 4), injections of 6 mg/kg levodopa methyl ester combined with 12.5 mg/kg benserazide (levodopa-treated groups, 3-day-treatment; n = 4, 7-day-treatment; n = 4, 14-day-treatment; n = 4), or injections of 6 mg/kg levodopa methyl ester with 12.5 mg/kg benserazide and 1 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin for 14 days (8-OH-DPAT-treated group; n = 4). We evaluated abnormal involuntary movement (AIM) scores and axon terminals in the GPi.

Results: The AIM score increased with levodopa treatment, as did the hypertrophy of axon terminals in the GPi, showing an increased number of synaptic vesicles in hypertrophied terminals.

Conclusion: Increased GABA storage in axon terminals of the direct pathway neurons represents the priming process of LID.

Keywords: GABA; abnormal involuntary movement; axon terminals; levodopa-treated rats; priming; synaptic plasticity; synaptic vesicles.

Grants and funding

This work was supported by JSPS KAKENHI Grant Number 20K16570 to HN, Interdisciplinary Collaborative Research Grant for Young Scientists of Hirosaki University to HN, and the Karoji Memorial Fund for Medical Research to HN.