Experimental parkinsonism induced by tetanus toxin injected into basal ganglia

Abstract

Background and Objectives: Local inhibitory circuits and long-range inhibitory projections within the interconnected basal ganglia nuclei are critical for control of voluntary movement and pathophysiology of different extrapyramidal movement disorders. Herein, we examined the major motor effects of tetanus neurotoxin (TeNT), a presynaptic neurotoxin that selectively targets the GABA-ergic synaptic transmission, when injected into individual basal ganglia nuclei. Methods: The rats were injected with low-dose TeNT (0.4-0.8 ng) unilaterally into globus pallidus internus (GPi), substantia nigra (SN), or caudate putamen (CPu). The effects of TeNT-induced disinhibition were characterized by repeated assessments of motor coordination, gait, and rotational behavior, followed by measurement of regional protein content of major neuronal monoaminergic, GABA-ergic and glutamatergic population markers. Results: In the beamwalk test, the CPu injection of TeNT induced contralateral plantar misplacement. TeNT injections into GPi and CPu were associated with decreased stride length and increased duration of step cycle and induced a slight ipsiversive circling during open field observation, and more intensive rotational behavior during swimming, differentially affected by D-amphetamine. Unlike rotational behavior, the gait and motor control deficits during beamwalk recovered promptly by day 14 post TeNT, which, along with the lack of reduced neuronal marker protein contents, suggested the reversibility and lack of neuronal degeneration. Conclusion and Implications: Tetanus toxin injected into basal ganglia evokes transient hypokinetic motor dysfunctions consistent with experimental parkinsonism, with differential occurrence of individual motor symptoms depending on the region targeted. These results suggest that TeNT might be a useful non-neurodegenerative pharmacological agent for investigating the motor control abnormalities involving GABA-ergic basal ganglia circuits.