The Influence of Striatal Astrocyte Dysfunction on Locomotor Activity in Dopamine-depleted Rats.

Introduction: Astrocyte dysfunction is the common pathology failing astrocyte-neuron interaction in neurological diseases, including Parkinson's Disease (PD). The present study aimed to evaluate the impacts of astrocytic dysfunction caused by striatal injections of selective glial toxin L-Aminoadipic Acid (L-AA) on the rats' locomotor activity in normal conditions and under alpha-methyl-p-tyrosine depletion of catecholamines synthesis. Methods: Thirty-three male Wistar rats were used in the experiments. Intrastriatal L-AA injections (100 μg) were performed into the right striatum. Alpha-methyl-p-tyrosine (a-MT, 100 mg/kg, inhibitor of tyrosine hydroxylase) was intraperitoneally injected for catecholamine depletion. The animals were divided into 5 groups, as follows: 1. L-AA treated (n=7), 2. L-AA+a-MT treated (n=5), 3. Sham-operated (n=7), 4. Sham+a-MT treated (n=5), 5. Intact control (n=9). For assessing motor function, open field and beam walking tests were used on the third day after the operation. Neuronal and astrocyte markers (glial fibrillary acidic protein, glutamine synthetase, tyrosine hydroxylase, & neuronal nuclear antigen) were examined in the striatum by immunohistochemistry. Results: Administrating L-AA led to astrocytic degeneration in the striatum. No neuronal death and disruption of dopaminergic terminals were detected. L-AA and a-MT-treated animals' distance traveled was significantly (P=0.047) shorter than the Sham-operated group injected with a-MT. In the walking beam test, the number of unilateral paw slippings was significantly (P<0.01) higher in the L-AA-treated group than Sham-operated animals. Administrating a-MT alone and L-AA did not change rats' performance in walking beam tests. Conclusion: Astrocyte ablation in dopamine depleted striatum resulted in reduced motor activity and asymmetrical gait disturbances. These findings demonstrated the role of astroglia in motor function regulation in the nigrostriatal system and suggest the possible association of glial dysfunction with motor dysfunction in PD. Highlights: The local administration of gliotoxin L-aminoadipate in the striatum of rats causes astrocytic degeneration without affecting the neurons and nigrostriatal fibers.The failure of astrocyte-neuron coupling in the striatum leads to motor dysfunction such as gait disturbances and bradykinesia.The influence of astrocytic degeneration on behavior is preserved and enhanced in dopamine-depleted rats. Plain Language Summary: Astrocytes are the nervous system's cells supporting the function of neurons. The failure of astrocyte-neuron interaction is observed in neurological diseases, including Parkinson's disease. We induced the aminoadipate-induced rat model of astrocytic dysfunction to evaluate the role of these cells in movement regulation. In our study, astrocytic dysfunction led to gait disturbances and impaired motor function. The results suggest a possible role of glial pathology in motor impairment in parkinsonism.