Habek, N. | Search bioRxiv

bioRxiv2024

Experimental parkinsonism induced by tetanus toxin injected into basal ganglia

Background and ObjectivesLocal 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. MethodsThe 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. ResultsIn 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 ImplicationsTetanus 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.

pharmacology and toxicology↗

bioRxiv2020

Selective vulnerability of supragranular layer neurons in schizophrenia

Schizophrenia is one of the most wide-spread mental brain disorders with complex and largely unknown etiology. To characterize the impact of schizophrenia at a cellular level, we performed single nucleus RNA sequencing of >190,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls (7 vs 11, respectively). In addition, to correlate data with cortical anatomy, >100,000 neurons were analyzed topographically by immunohistochemistry in an extended cohort of cases with schizophrenia and controls (10 vs 10). Compositional analysis of RNA sequencing data revealed reduction in relative abundance across all families of GABAergic neurons and a concomitant increase in principal neurons, which was most pronounced for supragranular subtypes (layers 2-3). Moreover, supragranular subtypes of GABAergic interneurons showed most dramatic transcriptomic changes. These results were substantiated by histological analysis, which revealed a reduction in the density of calretinin, calbindin and parvalbumin GABAergic interneurons particularly in layer 2. Common effect of schizophrenia on supragranular neuronal networks was underlined by downregulation of protein processing genes and upregulation of neuronal development/plasticity genes across supragranular subtypes of principal neurons and GABAergic interneurons. In situ hybridization and spatial transcriptomics further confirmed supragranular layer neuron vulnerability, revealing complexity of schizophrenia-affected cortical circuits. These point towards general network impairment within supragranular layers being a core substrate associated with schizophrenia symptomatology.

neuroscience↗