Hypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor

Abstract

Proteoglycans like syndecan-3 have complex signaling roles in addition to their function as structural components of the extracellular matrix. Here, we show that syndecan-3 in the lateral hypothalamus has an unexpected new role in limiting compulsive cocaine intake. In particular, we observe that syndecan-3 null mice self-administer greater amounts of cocaine than wild-type mice. This effect can be rescued by re-expression of syndecan-3 in the lateral hypothalamus with an adeno-associated viral vector. Adeno-associated viral vector delivery of syndecan-3 to the lateral hypothalamus also reduces motivation for cocaine in normal mice. Syndecan-3 limits cocaine intake by modulating the effects of glial-cell-line-derived neurotrophic factor, which uses syndecan-3 as an alternative receptor. Our findings indicate syndecan-3-dependent signaling as a novel therapeutic target for the treatment of cocaine addiction.

A Systems Approach to Drug Discovery in Alzheimer's Disease

“…Indeed, virtually none of the regulators that were experimentally validated were significantly differentially expressed at the RNA level and yet they were confirmed as individual or synergistic phenotypic drivers following identification by regulatory network analysis, thus elucidating novel mechanisms of disease initiation/ progression [4,12,13,[41][42][43][44][45][46], chemosensitivity [15,28], and normal physiologic regulation [14]. Lately, we have successfully extended these methodologies to the study of neurological, neurodevelopmental, and stem cell phenotypes [35,42,47], and, more recently, to neurodegenerative phenotypes, resulting in a series of manuscripts, currently in review, where we report on the elucidation and experimental validation of novel genes mediating neurotoxicity in ALS [48], as well as biomarkers of AD progression [9].…”

Neural ECM in addiction, schizophrenia, and mood disorder

“…Subsequent analysis of syndecan-3 À/À mice showed that a lack of this protein resulted in higher rates of cocaine self-administration, an effect that could be reversed by viral-mediated rescue of syndecan-3 in the lateral hypothalamus. In line with this, overexpression of syndecan-3 in the lateral hypothalamus of wild-type mice also decreased cocaine self-administration (Chen et al, 2013).…”

“…This is consistent with observations that plasticity-restricting PNN components are reduced after heroin self-administration (Van Den Oever et al, 2010) and protein expression of reelin is increased after cocaine self-administration (Host et al, 2010). Interestingly, an increasing number of studies show that experimental manipulations that reduce ECM breakdown or elevate ECM levels interfere with addictive behavior in different animal models of addiction, including behavioral sensitization (morphine, cocaine, and methamphetamine; Maiya et al, 2009;Mizoguchi et al, 2007;Nagai et al, 2004Nagai et al, , 2005b, CPP (morphine, cocaine, amphetamine, methamphetamine, and nicotine; Brown et al, 2007;Maiya et al, 2009;Mizoguchi et al, 2007;Nagai et al, 2004Nagai et al, , 2005bNagai et al, , 2006, cocaine self-administration (Chen et al, 2013), and reinstatement of heroine seeking (Van Den Oever et al, 2010). In contrast, enhancement of synaptic plasticity by ECM breakdown facilitates extinction of the drug memory (Xue et al, 2014), providing a substrate to suppress drug-seeking urges.…”

“…These results suggest that manipulation of neural levels of reelin, a protein involved in neurodevelopmental processes (e.g., neuronal migration) and adult synaptic plasticity (Frotscher, 2010;Gundelfinger et al, 2010), alters drug-taking and drug-seeking behavior. Syndecan-3 mRNA was upregulated in the lateral hypothalamus of rats after cocaine self-administration (Chen et al, 2013). Subsequent analysis of syndecan-3 À/À mice showed that a lack of this protein resulted in higher rates of cocaine self-administration, an effect that could be reversed by viral-mediated rescue of syndecan-3 in the lateral hypothalamus.…”

Role of perineuronal nets in the anterior dorsal lateral hypothalamic area in the acquisition of cocaine-induced conditioned place preference and self-administration

“…NARP is presynaptically secreted in a PNN dependent manner, recruiting AMPA receptors to cluster upon postsynaptic PV interneurons [85]. Expression of syndecan-3, a heparan sulfate proteoglycan component of the ECM that regulates ligand-receptor signaling, is induced by cocaine within the LH and significantly inhibits the motivation to self-administer cocaine [86]. Other candidate neuroplastic agents known to interact with PNNs include semphorin-3A, BDNF, and Otx2 [87–89].…”