Matrix Metalloproteinase-9 Overexpression Regulates Hippocampal Synaptic Plasticity and Decreases Alcohol Consumption
Li- Tian Yin1, Xiao-Yan Xie2, Lin-Yuan Xue2
1Key Laboratory for Cellular Physiology, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, 030001, Shanxi, China. yinlitian@126.com.
Abstract:
Brain matrix metalloproteinases (MMPs) have been recently implicated in alcohol addiction; however, the molecular mechanisms remain poorly understood. Matrix metalloproteinase-9 (MMP-9), an extrasynaptic protease, is the best described MMP that is thought to regulate addictive behavior. In the present study, the effect of MMP-9 overexpression on hippocampal neuron plasticity and alcoholic behavior was assessed in spontaneous alcohol drinking mice. Two-bottle choice model showed that the overexpression of MMP-9 in the hippocampus developed by adeno-associated virus (AAV) could decrease alcohol consumption and preference, but did not affect taste preference, which was tested using saccharin or quinine solutions. Dendritic spines number of hippocampal neurons was observed by Golgi staining. Compared with the alcohol treatment group, the density of dendritic spines in the hippocampus of alcohol drinking mice was decreased in alcohol + MMP-9 group. Western blot analysis indicated that GluN1 expression in the hippocampus of alcohol drinking group was lower than that in the control group, while the expression of GluN1 was increased in MMP-9 overexpressing mice. MMP-9 also regulated the depolymerization of actin filaments, which induced behavioral changes in mice. Taken together, overexpression of MMP-9 in the hippocampal neurons of mice resulted in decreased dendritic spine density and F-actin/G-actin ratio, which might be the crucial reason for the significant decrease in alcohol consumption in alcohol drinking mice. MMP-9 might be considered as a novel target studying the molecular mechanism of alcohol drinking.
Insights
Overexpressing matrix metalloproteinase-9 (MMP-9) in mouse hippocampus reduced alcohol consumption and preference. This suggests MMP-9 influences alcohol addiction by altering neuronal plasticity.
Area of Science:
- Neuroscience
- Molecular Biology
- Addiction Research
Background:
- Brain matrix metalloproteinases (MMPs) are implicated in alcohol addiction.
- The precise molecular mechanisms underlying MMPs' role in addiction are not fully understood.
- Matrix metalloproteinase-9 (MMP-9) is a key protease studied in relation to addictive behaviors.
Purpose of the Study:
- To investigate the effect of MMP-9 overexpression on hippocampal neuron plasticity.
- To assess the impact of MMP-9 on alcohol consumption and preference in mice.
- To elucidate the molecular mechanisms linking MMP-9, neuronal plasticity, and alcohol drinking behavior.
Main Methods:
- Adeno-associated virus (AAV) vector was used to overexpress MMP-9 in the hippocampus of spontaneous alcohol-drinking mice.
- Two-bottle choice tests were employed to measure alcohol consumption and preference, alongside taste preference tests (saccharin, quinine).
- Golgi staining was used to quantify dendritic spine density, and Western blot analysis measured GluN1 expression. Actin filament dynamics were also assessed.
Main Results:
- MMP-9 overexpression significantly decreased alcohol consumption and preference without affecting taste preference.
- Hippocampal neuron dendritic spine density was reduced in alcohol-drinking mice overexpressing MMP-9 compared to alcohol-treated controls.
- Overexpression of MMP-9 led to increased GluN1 expression in the hippocampus and regulated actin filament depolymerization.
Conclusions:
- Overexpression of MMP-9 in hippocampal neurons reduces dendritic spine density and alters the F-actin/G-actin ratio.
- These changes in neuronal plasticity are associated with a significant decrease in alcohol consumption.
- MMP-9 represents a potential novel therapeutic target for understanding and treating alcohol addiction.
