Matrix Metalloproteinase-9 Overexpression Regulates Hippocampal Synaptic Plasticity and Decreases Alcohol Consumption and Preference in Mice

Yin, Li Tian; Xie, Xiaoyan; Xue, Linyuan; Yang, Xiao Rong; Jia, Jingying; Zhang, Yu; Zhang, Ce

doi:10.1007/s11064-020-03053-8

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…Importantly, Pvb expression was significantly decreased in subjects with cocaine in their toxicology reports (Supplementary Figure 1G), suggesting that cocaine temporarily blunts PVB expression to disinhibit excitatory neurons 57 . Furthermore, decreased ECM proteolytic gene expression ( Mmp9 and Ctss ) in subjects with SUD is in line with increased PNN densities in these subjects and with preclinical models of hippocampal MMP9 expression in alcohol use 82 , potentially suggesting hypofunction of PNN proteolytic systems in SUD 83 . In our ANCOVA models, subjects with SUD who had cocaine in their toxicology reports had greater expression of Ctss (Supplementary Figure 1H).…”

Section: Discussionmentioning

confidence: 53%

Extracellular Matrix Abnormalities in the Hippocampus of Subjects with Substance Use Disorder

Valeri,

Stiplosek,

O’Donovan

et al. 2023

Preprint

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Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans (CSPGs) are a subset of ECM molecules that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest that modulation of PNNs may strengthen contextual reward memories in SUD. However, there is a lack of information regarding PNNs in the hippocampus of people with SUD as well as how comorbidity with major depressive disorder (MDD) may affect PNNs. We used postmortem hippocampal tissues from cohorts of human and nonhuman primates with or without chronic alcohol use to test the hypothesis that PNNs are increased in subjects with SUD. We used to histochemical labeling and quantitative microscopy to examine PNNs, and qRT-PCR to examine gene expression for ECM molecules, synaptic markers and related markers. We identified increased densities of PNNs and CSPG-labeled glial cells in SUD, coinciding with decreased mRNA expression of the ECM protease matrix metalloproteinase 9 (MMP9), and increased expression for the excitatory synaptic marker vesicle associated membrane protein 2 (VAMP2). Similar increases in PNNs were observed in monkeys with chronic alcohol self-administration. Subjects with MDD displayed changes opposite to SUD, and subjects with SUD and comorbid MDD had minimal changes in any of the outcome measures examined. Our findings demonstrate that PNNs are increased in SUD, possibly contributing to stabilizing contextual reward memories as suggested by preclinical studies. Our results also point to a previously unsuspected role for CSPG expression in glial cells in SUD. Evidence for increased hippocampal PNNs in SUD suggests that targeting PNNs to weaken contextual reward memories is a promising therapeutic approach for SUD, however comorbidity with MDD is a significant consideration.

show abstract

Section: Discussionmentioning

confidence: 53%

Extracellular Matrix Abnormalities in the Hippocampus of Subjects with Substance Use Disorder

Valeri,

Stiplosek,

O’Donovan

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Importantly, Pvb expression was significantly decreased in subjects with cocaine in their toxicology reports (Supplementary Figure 1G ), suggesting that cocaine temporarily blunts PVB expression to disinhibit excitatory neurons [ 56 ]. Furthermore, decreased ECM proteolytic gene expression ( Mmp9 and Ctss ) in subjects with SUD is in line with increased PNN densities in these subjects and with preclinical models of hippocampal MMP9 expression in alcohol use [ 80 ], potentially suggesting hypofunction of PNN proteolytic systems in SUD [ 81 ]. In our ANCOVA models, subjects with SUD who had cocaine in their toxicology reports had greater expression of Ctss (Supplementary Figure 1H ).…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix abnormalities in the hippocampus of subjects with substance use disorder

Valeri,

Stiplosek,

O’Donovan

et al. 2024

Transl Psychiatry

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Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans (CSPGs) are a subset of ECM molecules that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest that modulation of PNNs may strengthen contextual reward memories in SUD. However, there is currently a lack of information regarding PNNs in the hippocampus of people with SUD as well as how comorbidity with major depressive disorder (MDD) may affect PNNs. We used postmortem hippocampal tissues from cohorts of human and nonhuman primates with or without chronic alcohol use to test the hypothesis that PNNs are increased in subjects with SUD. We used histochemical labeling and quantitative microscopy to examine PNNs, and qRT-PCR to examine gene expression for ECM molecules, synaptic markers and related markers. We identified increased densities of PNNs and CSPG-labeled glial cells in SUD, coinciding with decreased expression of the ECM protease matrix metalloproteinase 9 (Mmp9), and increased expression for the excitatory synaptic marker vesicle associated membrane protein 2 (Vamp2). Similar increases in PNNs were observed in monkeys with chronic alcohol self-administration. Subjects with MDD displayed changes opposite to SUD, and subjects with SUD and comorbid MDD had minimal changes in any of the outcome measures examined. Our findings demonstrate that PNNs are increased in SUD, possibly contributing to stabilizing contextual reward memories as suggested by preclinical studies. Our results also point to a previously unsuspected role for CSPG expression in glial cells in SUD. Evidence for increased hippocampal PNNs in SUD suggests that targeting PNNs to weaken contextual reward memories is a promising therapeutic approach for SUD, however comorbidity with MDD is a significant consideration.

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“…Abnormal morphology and density of dendritic spines could be observed in patients and animals with addiction ( Beltran-Campos et al, 2015 ; Yin et al, 2020 ), accompanied by abnormal expression and activation level of Rho GTPase and its regulatory factors ( Cahill et al, 2018 ). Regulation of Rho GTPase activities is very crucial for treating substance dependence ( Table 2 ).…”

Section: Rho Gtpases and Substance Dependencementioning

confidence: 99%

The potential therapeutic roles of Rho GTPases in substance dependence

Wang

Zhou

et al. 2023

Front. Mol. Neurosci.

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Rho GTPases family are considered to be molecular switches that regulate various cellular processes, including cytoskeleton remodeling, cell polarity, synaptic development and maintenance. Accumulating evidence shows that Rho GTPases are involved in neuronal development and brain diseases, including substance dependence. However, the functions of Rho GTPases in substance dependence are divergent and cerebral nuclei-dependent. Thereby, comprehensive integration of their roles and correlated mechanisms are urgently needed. In this review, the molecular functions and regulatory mechanisms of Rho GTPases and their regulators such as GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in substance dependence have been reviewed, and this is of great significance for understanding their spatiotemporal roles in addictions induced by different addictive substances and in different stages of substance dependence.

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Matrix Metalloproteinase-9 Overexpression Regulates Hippocampal Synaptic Plasticity and Decreases Alcohol Consumption and Preference in Mice

Cited by 7 publications

References 49 publications

Extracellular Matrix Abnormalities in the Hippocampus of Subjects with Substance Use Disorder

Extracellular Matrix Abnormalities in the Hippocampus of Subjects with Substance Use Disorder

Extracellular matrix abnormalities in the hippocampus of subjects with substance use disorder

The potential therapeutic roles of Rho GTPases in substance dependence

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