Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein

Area of Science:

• Neuroscience
• Pathology
• Molecular Biology

Background:

• Abnormal cortical network excitability is observed in Alzheimer's disease (AD) and other neurodegenerative conditions.
• It remains unclear if alpha-synucleinopathies, such as dementia with Lewy bodies (DLB), share this hyperexcitability as a core feature.

Purpose of the Study:

• To investigate network excitability in murine models of DLB expressing human mutant or wild-type alpha-synuclein (α-syn).
• To determine if α-synucleinopathy is associated with early-onset network hyperexcitability.

Main Methods:

• Utilized two mouse models of DLB expressing human mutant (hA30P) or wild-type (hWT-α-syn) α-syn.
• Performed in vitro electrophysiological recordings (extracellular local field potentials, intracellular recordings) and in vivo behavioral tests (open field test).
• Conducted quadruple immunohistochemistry for α-syn and mitochondrial markers in parvalbumin-expressing interneurons.

Main Results:

• Observed network hyperexcitability, evidenced by interictal discharges (IIDs), in young, pre-symptomatic transgenic α-syn mice.
• Found a lower concentration of the GABA(A) receptor antagonist (gabazine) required to evoke IIDs in hA30P mice compared to controls.
• Noted increased locomotor activity and a more depolarized resting membrane potential in CA3 pyramidal cells of hA30P mice.
• Detected human α-syn in 25% of parvalbumin-positive (PV+) interneurons and increased COX1 expression in these cells in hA30P mice, without altering PV expression.

Conclusions:

• Hippocampal network hyperexcitability may be an early consequence of α-syn-mediated impairment of neuronal/synaptic function in DLB.
• This hyperexcitability occurs without significant loss of PV+ interneurons.
• Targeting network excitability early in the disease stage warrants exploration for treating α-synucleinopathies like DLB.