Sex-dependent neuronal effects of α-synuclein reveal that GABAergic transmission is neuroprotective of sleep-controlling neurons

Altair Brito Dos Santos; Siganya Thaneshwaran; Lara Kamal Ali; César Ramón Romero Leguizamón; Yang Wang; Morten Pilgaard Kristensen; Annette E Langkilde; Kristi A Kohlmeier

doi:10.1186/s13578-023-01105-4

Sex-dependent neuronal effects of α-synuclein reveal that GABAergic transmission is neuroprotective of sleep-controlling neurons

Cell Biosci. 2023 Sep 14;13(1):172. doi: 10.1186/s13578-023-01105-4.

Authors

Altair Brito Dos Santos^{1

2}, Siganya Thaneshwaran¹, Lara Kamal Ali¹, César Ramón Romero Leguizamón¹, Yang Wang¹, Morten Pilgaard Kristensen³, Annette E Langkilde¹, Kristi A Kohlmeier⁴

Affiliations

¹ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark.
² Dept of Neuroscience, University of Copenhagen, Copenhagen, 2200, Denmark.
³ Academic Services, Vaerløse, 3500, Denmark.
⁴ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark. kak1@sund.ku.dk.

Abstract

Background: Sleep disorders (SDs) are a symptom of the prodromal phase of neurodegenerative disorders that are mechanistically linked to the protein α-synuclein (α-syn) including Parkinson's disease (PD). SDs during the prodromal phase could result from neurodegeneration induced in state-controlling neurons by accumulation of α-syn predominant early in the disease, and consistent with this, we reported the monomeric form of α-syn (monomeric α-syn; α-syn_M) caused cell death in the laterodorsal tegmental nucleus (LDT), which controls arousal as well as the sleep and wakefulness state. However, we only examined the male LDT, and since sex is considered a risk factor for the development of α-syn-related diseases including prodromal SDs, the possibility exists of sex-based differences in α-syn_M effects. Accordingly, we examined the hypothesis that α-syn_M exerts differential effects on membrane excitability, intracellular calcium, and cell viability in the LDT of females compared to males.

Methods: Patch clamp electrophysiology, bulk load calcium imaging, and cell death histochemistry were used in LDT brain slices to monitor responses to α-syn_M and effects of GABA receptor acting agents.

Results: Consistent with our hypothesis, we found differing effects of α-syn_M on female LDT neurons when compared to male. In females, α-syn_M induced a decrease in membrane excitability and heightened reductions in intracellular calcium, which were reliant on functional inhibitory acid transmission, as well as decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) with a concurrent reduction in action potential firing rate. Cell viability studies showed higher α-syn_M-mediated neurodegeneration in males compared to females that depended on inhibitory amino acid transmission. Further, presence of GABA receptor agonists was associated with reduced cell death in males.

Conclusions: When taken together, we conclude that α-syn_M induces a sex-dependent effect on LDT neurons involving a GABA receptor-mediated mechanism that is neuroprotective. Understanding the potential sex differences in neurodegenerative processes, especially those occurring early in the disease, could enable implementation of sex-based strategies to identify prodromal PD cases, and promote efforts to illuminate new directions for tailored treatment and management of PD.

Keywords: Cholinergic; Laterodorsal Tegmentum; Sleep disorders; α -synucleinopathies, neurodegenerative disease.