Morpho-Functional Changes of Nigral Dopamine Neurons in an α-Synuclein Model of Parkinson’s Disease

A B S T R A C T : Background: The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson’s disease (PD). Although several aspects linked to α-syn–dependent pathology (con- cerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particu- larly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression. Objectives: We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons. Methods: We performed immunohistochemistry, stereo- logical DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA micro- dialysis measurements in a 12- to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca+/+) and age-matched wild-type rats. Results: Aged Snca+/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/ inactivating voltage-gated K+ channels and Ca2+- and voltage-activated large conductance K+ channels. These intrinsic currents underlie the repolarization/ afterhyperpolarization phase of action potentials, thus affecting neuronal excitability. Conclusions: Besides clarifying α-syn–induced patho- logical landmarks, such evidence reveals compensa- tory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neu- rodegeneration. © 2022 The Authors. Movement Disor- ders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.