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

Abstract

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.

Choice impulsivity after repeated social stress is associated with increased perineuronal nets in the medial prefrontal cortex

“…We also show here that stressed animals had an increased density of PNNs in the mPFC compared to controls. PNNs are extracellular matrix structures that play a key role in neuronal plasticity and enhance the activity of PV cells, and, in turn, cortical inhibitory activity 41 – 44 , 56 . Previous studies have shown that chronic stress increases the expression of PNNs and the activity of PV interneurons in the mPFC, and that these effects are associated with stress-induced behavioral deficits 34 , 37 .…”

“…In support of this suggestion, it has been shown that chronic stress increases the number of parvalbumin GABA inhibitory interneurons (PV) 37 in the mPFC, and that increasing/decreasing the activity of PV cells or the expression of perineuronal nets (PNNs) in the mPFC reverses the behavioral deficits produced by stress 35 , 38 – 41 . PNNs are extracellular matrix structures that enhance the inhibitory activity of cortical PV cells 41 – 44 . Based on this evidence, in the current study we first determined whether ISD alters delay discounting behavior, and second, whether ISD changes cortical inhibitory function.…”

Perineuronal Nets in the CNS: Architects of Memory and Potential Therapeutic Target in Neuropsychiatric Disorders

“…Increased densities of hippocampal PNNs, coupled with decreased ECM proteolytic genes and altered synaptic markers, support preclinical studies indicating that PNNs may stabilize reward memories. PNNs and ECM molecules may be promising targets for addressing cue-induced relapse in SUD [ 141 ]. In summary, PNN removal appears to create a blank slate for neuroplasticity that has the potential to combat drug-induced maladaptive plasticity and create new adaptive response, suggesting that targeting PNNs may be promising for the treatment of addiction.…”

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence

“…The rapid progress of PNN studies in a range of brain disease models highlights the prospects of PNN pharmacological targeting as a new medication approach [62,144,168,169]. Microscopy techniques may be highly instrumental in addressing PNN medical pharmacology both in terms of high-throughput drug lead screening and for the high-resolution investigation of drug targeting and effects at a single-synapse level.…”