Compensatory Mechanisms and T Cell Migration In Mouse Models of Dopaminergic Loss

We previously showed that chronic administration for 35 days of L-3,4dihydroxyphenylalanine (L-DOPA) or BL-1023 [an L-DOPA-gamma-aminobutyric acid (GABA) conjoined compound] improved locomotor function and increased numbers of tyrosine hydroxylase (TH) immunoreactive (TH+) neurons in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice compared to those given no drug. We therefore sought to identify whether the increase in TH+ neurons was a consequence of neurogenesis or rather from a phenotypic shift of surviving neurons in the substantia nigra. Using the thymidine analogue bromodeoxyuridine (BrdU), we sought to identify newly formed neurons after 21 days of L-DOPA or BL-1023 treatment, but were unable to do so. Dual immunofluorescent analysis of tissues for TH and glutamic acid decarboxylase-67 (GAD67), a marker for GABAergic neurons revealed that mice treated with either L-DOPA or BL-1023 showed significant increases in the numbers of TH+GAD67+ neurons in the substantia nigra compared to controls. These findings support the notion that numbers of GAD67+ neurons upregulate TH expression and effectively increase the numbers of TH+ neurons in response to MPTP-intoxication, loss of dopaminergic neurons, and/or chronic administration of dopamine-replacement drugs.