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

Area of Science:

• Neuroscience
• Molecular Biology
• Addiction Research

Background:

• Contextual triggers significantly contribute to relapse in substance use disorders (SUD).
• Extracellular matrix (ECM) molecules, particularly chondroitin sulfate proteoglycans (CSPGs) forming perineuronal nets (PNNs), are implicated in mediating reward memories.
• PNNs regulate synaptic plasticity and stability, but their role in human SUD, especially with major depressive disorder (MDD) comorbidity, is understudied.

Approach:

• Utilized postmortem hippocampal tissues from human and nonhuman primate cohorts with and without chronic alcohol exposure.
• Employed histochemical labeling and quantitative microscopy to assess PNN densities and CSPG-expressing glial cells.
• Conducted qRT-PCR to analyze gene expression of ECM molecules, synaptic markers (e.g., VAMP2), and related factors (e.g., MMP9).

Key Points:

• Increased PNN densities and CSPG-labeled glial cells were observed in subjects with SUD.
• Expression of the ECM protease matrix metalloproteinase 9 (Mmp9) decreased, while the excitatory synaptic marker vesicle associated membrane protein 2 (Vamp2) increased in SUD.
• Similar PNN increases were found in nonhuman primates with chronic alcohol self-administration.
• Major depressive disorder (MDD) showed opposite changes, and comorbid SUD and MDD exhibited minimal alterations.

Conclusions:

• Findings demonstrate elevated hippocampal PNNs in SUD, potentially reinforcing contextual reward memories, aligning with preclinical findings.
• CSPG expression in glial cells emerges as a novel factor in SUD.
• Increased hippocampal PNNs in SUD suggest PNNs as a potential therapeutic target for weakening reward memories, though MDD comorbidity requires careful consideration.