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TMEM168, a new player in mood disorders?

Transcriptional studies have revealed that alterations of gene expression are key mechanisms by which stimuli induce adaptive modifications in the brain. Indeed, these changes have been associated with the development of behavioral abnormalities.
Several molecular actors have been shown to be dramatically associated with genetic and behavioral alterations resulting from psychiatric and neurological disorders, such as BDNF, nuclear factor-κB, ΔFosB, tumor necrosis factor-α, and many others. However, the exact neuronal circuits, as well as the involvement of novel molecular cascades relevant to such complex phenomena, remain elusive and deserve in-depth investigations.
In a recent PLOS One article, Fu and colleagues reported the involvement of TMEM168 (transmembrane protein 168) in the etiology of anxiety and sensorimotor gating deficits.

TMEM168, a newly discovered transmembrane protein, has been observed to be increased in the nucleus accumbens (NAc) of methamphetamine-treated animals (Fu et al., 2017). The NAc is a key region of the reward system, which is very sensitive to adaptive changes. Interestingly, the NAc has also been pointed as a master regulator of mood disorders such as depression and anxiety. Taking advantage of viral approaches and behavioral tasks, the group of Atsuma Nitta (University of Toyama, Japan) has found that overexpression of TMEM168 specifically in the NAc was able to promote aberrant behaviors. A series of behavioral tests were performed to detect changes in emotional behavior induced by TMEM168 overexpression. Virus-mediated overexpression of TMEM168 in the NAc did not alter locomotor activity, cognitive ability, social interaction, or depression-like behaviors in mice. Surprisingly, the authors observed increased anxiety in the elevated plus-maze and light/ dark box tasks following TMEM168 overexpression. The basic premise of most of these anxiety-related models is that the set of behavioral responses induced by exposure to a novel (and stressful) environment, which simultaneously evokes fear and curiosity, creates a typical approach-avoidance conflict. In addition, a sensorimotor gating deficit in the auditory prepulse inhibition (PPI) task was detected following TMEM168 overexpression. This test measures pre-attentive processes that operate outside of conscious awareness and is widely used in animal models of diseases marked by an inability to inhibit, or “gate” irrelevant information in sensory, motor, or cognitive domains. “These findings”, conclude Fu, “suggest that TMEM168 in the NAc is crucial for the modulation of anxiety and schizophrenia-like behaviors in mice”.

From a neurochemical point of view, the NAc is mainly composed of GABAergic cells and GABA is a primary inhibitory neurotransmitter associated with the regulation of emotional states, including anxiety and panic disorders. Specifically, the reduced concentration of GABA is thought to be associated with increased anxiety levels. Using in vivo microdialysis analysis, Fu and colleagues observed that the basal levels of extracellular GABA were reduced in the NAc, and GABA release was also reduced after K+ stimulation in the NAc-TMEM168 mice when compared with their control mice. Furthermore, the pharmacological action of diazepam, a therapeutic molecule known to facilitate GABAergic transmission by binding GABAA receptors, reversed the TMEM168 overexpression-induced anxiety as measured in both the elevated plus-maze and light/dark box paradigms. “These results suggest that a reduction in GABAergic neurotransmission could be linked to TMEM168-induced anxious behaviors”, says Kequan Fu, the leading author of the article.
The direct targets of the accumbal projections, notably the ventral tegmental area and pallidum, are demonstrated to be relevant to anxiety-like symptoms via GABAergic dysfunction. Thus, according to the authors, “the interrupted GABAergic projection from the NAc might underlie the mechanism of the increased anxiety in the NAc-TMEM mice”.

In a previous study, the same authors found that extracellular osteopontin (OPN) was increased in the NAc-TMEM mice (Fu et al., 2017). Activation of integrin receptors is usually determined as the downstream signaling pathway of the secreted OPN and mutations of β1- and β3-containing integrins in mice have been associated with anxiety-like disorders (Park and Goda, 2016). “Thus, the TMEM168-OPN-integrin receptor could also be implicated in the mechanisms underpinning TMEM168-mediated effects on behavior”, conclude the authors.

Despite these exciting results, the downstream signaling pathways of TMEM168 in gating GABAergic activity or behavioral events still remain unclear. In fact, given the profound cellular heterogeneity of the NAc (D1R-MSNs, D2R-MSNs, interneurons, astrocytes, etc), one could wonder which cell type may be responsible for TMEM168-mediated effects. Indeed, future investigations will be necessary to fully explore the role of TMEM168 in accumbal circuits.

Image credit : flickr

Any views expressed are those of the author, and do not necessarily reflect those of PLOS. 

Peppe-BWGiuseppe Gangarossa received his PhD in Biomedical Sciences, specialty Neuroscience, from the University of Bologna. He has been a visiting fellow at the Karolinska Institutet (Sotckholm, Sweden), the French Inserm (Montpellier, France) and the Collège de France (Paris, France). Giuseppe is currently Assistant Professor of Physiology at the University Paris Diderot. His main research topic is dopamine-related brain disorders. You can follow him on twitter @PeppeGanga

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