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Published on: August 16, 2020
α-synuclein-lack expression rescues methamphetamine-induced mossy fiber degeneration in dorsal hippocampal CA3
Jiuyang Ding1, Jun Wu2, Xiaotao Hou3
1School of Forensic Medicine, Guizhou Medical University, Guiyang, China; Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, China.
Abstract:
Methamphetamine (METH) - induced cognitive impairments may be related to synaptic degeneration at mossy fiber terminals, critical for spatial memory formation in hippocampal circuits. We have previously found METH-induced neurodegeneration in the striatum by increasing the α-synuclein (α-SYN) level. However, whether and how the METH-induced mossy fiber degeneration is also blamed for the abnormal accumulation of α-SYN remains to be elucidated. Chronic METH exposure decreased mossy fiber density but upregulatedα-SYN and phosphorylated TAU (TAU-pSer396) in hippocampal CA3, associated with glial cell overactivation, axonal neuropathies, and memory impairment. Notably, the knockout of the α-SYN gene significantly alleviated the METH-induced mossy fiber degeneration and memory impairment. Meanwhile, the TAU-pSer396 accumulation and glial activation were ameliorated by α-SYN knockout. Our findings suggest an essential role of α-SYN in mediating METH-induced mossy fiber degeneration, providing promising therapeutic and prophylactic targets for METH-related neurodegenerative diseases.
Insights
Methamphetamine (METH) causes cognitive decline by damaging hippocampal mossy fibers. Alpha-synuclein (α-SYN) accumulation drives this METH-induced degeneration and memory loss, offering potential therapeutic targets.
Area of Science:
- Neuroscience
- Neuropharmacology
- Synaptic Plasticity
Background:
- Methamphetamine (METH) use is linked to cognitive impairments, potentially due to synaptic damage in hippocampal circuits crucial for memory.
- Previous research identified METH-induced striatal neurodegeneration associated with increased alpha-synuclein (α-SYN) levels.
Purpose of the Study:
- To investigate the role of α-SYN in METH-induced mossy fiber degeneration in the hippocampus.
- To determine the impact of chronic METH exposure on mossy fiber density, α-SYN, and phosphorylated TAU (TAU-pSer396) levels.
Main Methods:
- Chronic METH exposure in a mouse model.
- Assessment of mossy fiber density, α-SYN, and TAU-pSer396 levels in the hippocampus.
- Evaluation of glial cell activation and axonal integrity.
- Behavioral testing for memory impairment.
- Utilizing α-SYN knockout mice for mechanistic studies.
Main Results:
- Chronic METH exposure reduced mossy fiber density and upregulated α-SYN and TAU-pSer396 in the hippocampal CA3 region.
- METH-induced changes were associated with glial cell overactivation, axonal neuropathies, and memory deficits.
- Knockout of the α-SYN gene significantly attenuated METH-induced mossy fiber degeneration and memory impairment.
- α-SYN knockout also ameliorated TAU-pSer396 accumulation and glial activation.
Conclusions:
- Alpha-synuclein (α-SYN) plays a critical role in mediating methamphetamine-induced mossy fiber degeneration.
- Targeting α-SYN may offer a promising therapeutic strategy for METH-related neurodegenerative diseases and cognitive impairments.
