Role of Protein Shisa7 in Addiction Behavior Uncovered

The rising epidemic of opioid addiction presents a significant public health challenge, with opioid-related overdose deaths occurring approximately every 90 seconds worldwide. Recent research has highlighted the potential involvement of the SHISA7 gene in addiction mechanisms, particularly concerning heroin, a potent semi-synthetic opioid.

Each year, opioid use disorder (OUD) claims over 350,000 lives globally, prompting urgent calls for effective treatment strategies. Most current pharmacological interventions focus primarily on the rewarding aspects of substance use. However, emerging evidence suggests that drug-seeking behaviors and cognitive impairments, mediated by the orbitofrontal cortex (OFC), also play crucial roles in addiction.

A research team from the Friedman Brain Institute at Mount Sinai has embarked on a novel approach to identify biomolecules critical to understanding the complexities of addiction. Their study utilized machine learning techniques to analyze the OFC transcriptome in post-mortem brain samples from individuals with heroin dependency, with findings published in the journal Biological Psychiatry.

The researchers isolated RNA from OFC samples of 34 deceased heroin users and compared it to 28 control samples. Through differential gene expression analysis, the team consistently identified SHISA7 as a significant predictor of heroin use. Notably, the heroin group exhibited a downregulation of SHISA7, a gene that has previously received limited attention.

The protein product of SHISA7 is believed to act as a modulator of GABAA and/or AMPA receptors, which are integral to neurotransmission. In animal models, chronic exposure to heroin resulted in a significant reduction of SHISA7 expression in the OFC, correlating positively with heroin-seeking behavior observed in the rats. Interestingly, a single exposure to heroin did not elicit any noticeable effects.

To further investigate the functional implications of SHISA7, the researchers employed lentiviral overexpression techniques in the OFC of heroin-experienced animals. This manipulation significantly heightened heroin-associated seeking behaviors and impaired the animals' ability to shift their preferences towards natural rewards, such as sucrose, indicating reduced cognitive flexibility--a hallmark of opioid use disorder.

Following SHISA7 overexpression, the OFC of rats exhibited gene expression patterns that closely resembled those of heroin-exposed subjects and human heroin users, particularly in the context of neuroinflammatory and neurodegenerative signaling pathways. The study highlighted that, in the presence of heroin, SHISA7 overexpression markedly intensified these transcriptional profiles.

In further investigations, the research team utilized co-immunoprecipitation and mass spectrometry to examine the molecular interactions involving SHISA7. These methods allowed for the identification of protein complexes that interact with SHISA7, revealing connections to glutamatergic and GABAergic receptor subtypes, as well as proteins implicated in synaptic structure, glial cell functions, and neurocognitive disorders.

The findings suggest that SHISA7 in the OFC plays a pivotal role in behaviors associated with addiction and their molecular regulation. The downregulation of the SHISA7 gene following heroin exposure, while the protein product itself enhances addictive behaviors, implies a protective mechanism that, when disrupted, may lead to heightened heroin dependency. Overall, these results indicate that SHISA7 influences both neuroinflammatory and synaptic networks, positioning it as a potential target for innovative therapeutic interventions in opioid use disorder and related neuropsychiatric conditions.