Progressive tremor and motor impairment in seizure-prone mutant tremor mice are associated with neurotransmitter dysfunction

The tremor mutant mice present motor impairments comprised of whole-body tremors, ataxia, decreased exploratory behavior, and audiogenic seizures. This study aims to investigate the development of motor dysfunction in this mutant mouse and the relationships with cortical, striatal, and cerebellar le...

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Published in:	Behavioural brain research Vol. 443; p. 114329
Main Authors:	Gonçalves, Flávio B., Garcia-Gomes, Mariana S.A., Silva-Sampaio, Ana Claudia, Kirsten, Thiago B., Bondan, Eduardo F., Sandini, Thaísa M., Flório, Jorge C., Lebrun, Ivo, Coque, Alex de C., Alexandre-Ribeiro, Sandra R., Massironi, Silvia M.G., Mori, Claudia M.C., Bernardi, Maria M.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 12-04-2023
Subjects:	Animals Aspartic Acid - metabolism Corpus Striatum - metabolism Development Dopamine Dopamine - metabolism gamma-Aminobutyric Acid - metabolism Glutamic Acid - metabolism Glycine - metabolism Mice Motor Disorders Motor dysfunction Mutation Neurotransmitter Agents - metabolism Norepinephrine - metabolism Seizures - metabolism Serotonin - metabolism Serotonin, glycine Tremor - metabolism Development Serotonin, glycine Dopamine Mutation Motor dysfunction
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Summary:	The tremor mutant mice present motor impairments comprised of whole-body tremors, ataxia, decreased exploratory behavior, and audiogenic seizures. This study aims to investigate the development of motor dysfunction in this mutant mouse and the relationships with cortical, striatal, and cerebellar levels of GABA, glutamate, glycine, dopamine (DA), serotonin (5-HT), noradrenaline (NOR), and its metabolites. The serum cytokines levels, myelin content, and the astrocytic expression of the glial fibrillary acidic protein (GFAP) investigated the possible influence of inflammation in motor dysfunction. Relative to wild-type (WT) mice, the tremor mice presented: increased tremors and bradykinesia associated with postural instability, decreased range of motion, and difficulty in initiating voluntary movements directly proportional to age; reduced step length for right and left hindlimbs; reduced cortical GABA, glutamate and, aspartate levels, the DOPAC/DA and ratio and increased the NOR levels; in the striatum, the levels of glycine and aspartate were reduced while the HVA levels, the HVA/DA and 5HIAA/5-HT ratios increased; in the cerebellum the glycine, NOR and 5-HIAA levels increased. We suggest that the motor disturbances resulted mainly from the activation of the indirect striatal inhibitory pathway to the frontal cortex mediated by GABA, glutamate, and aspartate, reducing the dopaminergic activity at the prefrontal cortex, which was associated with the progressive tremor. The reduced striatal and increased cerebellar glycine levels could be partially responsible for the mutant tremor motor disturbances. [Display omitted] •The audiogenic mutant tremor mice showed motor function impairment.•Proportional to age, tremor mice had increased tremors, bradykinesia, and postural instability.•Tremor mice presented reduced cortical GABA, glutamate, and aspartate levels.•Tremor mice had decreased striatal and increased cerebellar glycine levels•Tremor was related to striatal inhibitory pathway to the frontal cortex and striatal and cerebellar glycine.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0166-4328 1872-7549
DOI:	10.1016/j.bbr.2023.114329