The circuit and synaptic organization of the basal ganglia output : mechanistic insights on movement disorders and action control

Understanding the neural circuitry underlying movement is a neuroscientific challenge that promises to help refining currently available treatments for movement disorders. Key structures for movement and action control are the basal ganglia nuclei, whose complexity has only just started to be resolved. The constituent papers of this thesis analyzed different levels of basal ganglia circuit organization and function.

In paper 1 we used a 6-hydroxydopamine (6-OHDA) lesion model of Parkinson’s Disease (PD) to study glutamatergic synapses in the substantia nigra reticulata (SNr). We found that NMDA receptors synaptic function in the SNr is altered in 6-OHDA lesioned mice. NMDA receptor blockade transiently rescued hypolocomotion in 6-OHDA lesioned mice. In paper 2 we used a mutated Leucin Rich Repeat Kinase 2 (LRRK2-G2019S) mouse model and studied midbrain adaptations in a middle age range that precedes the onset of neurodegeneration. LRRK2-G2019S mice had increased exploratory behavior compared to their wild-type littermate. In midbrain dopamine neurons glutamatergic neurotransmission was affected in a region-specific manner, but no change in firing was identified. In paper 3 we used the same model to investigate the firing and glutamatergic synapses of SNr neurons. We found no change in firing whereas glutamate release but not N-Methyl-D-Aspartate (NMDA) receptors was altered in SNr neurons. In paper 4 we analyzed the organization of synaptic inputs to the associative and sensorimotor SNr. We found that inputs from the direct pathway are homogeneously distributed across SNr subregions whereas inputs from the indirect pathway are biased to the sensorimotor SNr. In alcohol exposed mice, inputs from the sensorimotor striatum were selectively potentiated. In paper 5 we focused on the indirect pathway projections to the globus pallidus external segment and identified distinct mechanisms of presynaptic modulation by cannabinoid 1 (CB1) and GABAB receptors.

In summary, we have investigated several basal ganglia circuits and their synaptic adaptations in disease models. We revealed key features of the SNr circuit organization and its adaptations in mouse models of PD. We found that distinct subpopulations of SNr neurons are part of the associative and sensorimotor loops, and that direct and direct pathway inputs are differentially integrated in these neurons. These findings are relevant to understanding how the SNr shapes the behavioral output of the basal ganglia circuits. In mouse models of PD and alcohol use disorder the synaptic inputs to the SNr are reorganized. These findings open novel views and research directions on the functional organization of the basal ganglia output.

List of scientific papers

I. NMDA receptors are altered in the substantia nigra reticulata and their blockade ameliorates motor deficits in experimental parkinsonism. Sitzia G., Mantas I., Zhang X., Svenningsson P., Chergui K. Neuropharmacology. 2020 Sep 1;174:108136.
https://doi.org/10.1016/j.neuropharm.2020.108136

II. LRRK2-G2019S mice display alterations in glutamatergic synaptic transmission in midbrain dopamine neurons. Skiteva O., Yao N., Sitzia G., Chergui K. J Neurochem. 2022 Apr;161(2):158-172.
https://doi.org/10.1111/jnc.15588

III. Neuronal firing and glutamatergic synapses in the substantia nigra pars reticulata of LRRK2-G2019S mice. Sitzia G., Skiteva O., Chergui K. [Manuscript]

IV. Input-specific plasticity on distinct basal ganglia output subdomains underlies action performance deficits following chronic ethanol exposure. Sitzia G., Bariselli S., Gracias A., Lovinger DM. [Manuscript]

V. Distinct mechanisms of CB1 and GABAB receptor presynaptic modulation of striatal indirect pathway projections to mouse Globus Pallidus. Sitzia G., Abrahao KP., Liput D., Calandra GM., Lovinger DM. [Manuscript]