Lateral habenula dysfunctions in Tm4sf2−/y mice model for neurodevelopmental disorder

Abstract

Mutations in the TM4SF2 gene, which encodes TSPAN7, cause a severe form of intellectual disability (ID) often comorbid with autism spectrum disorder (ASD). Recently, we found that TM4SF2 loss in mice affects cognition. Here, we report that Tm4sf2 −/y mice, beyond an ID-like phenotype, display altered sociability, increased repetitive behaviors, anhedonic- and depressive-like states. Cognition relies on the integration of information from several brain areas. In this context, the lateral habenula (LHb) is strategically positioned to coordinate the brain regions involved in higher cognitive functions. Furthermore, in Tm4sf2 −/y mice we found that LHb neurons present hypoexcitability, aberrant neuronal firing pattern and altered sodium and potassium voltage-gated ion channels function. Interestingly, we also found a reduced expression of voltage-gated sodium channel and a hyperactivity of the PKC-ERK pathway, a well-known modulator of ion channels activity, which might explain the functional phenotype showed by Tm4sf2 −/y mice LHb neurons. These findings support Tm4sf2 −/y mice as useful in modeling some ASD-like symptoms. Additionally, we can speculate that LHb functional alteration in Tm4sf2 −/y mice might play a role in the disease pathophysiology.

Tetraspanin 7 regulates osteoclast function through association with the RANK/αvβ3 integrin complex

“…Previous reports revealed that integrins are involved in signal transduction by interacting with TSPANs (Bassani & Cingolani, 2012; Hemler, 2005; Yanez‐Mo et al, 2009). Specifically, TSPAN7 influences actin remodeling by forming complexes with β1 integrin, PICK1, and AMPAR in hippocampal neurons (Bassani et al, 2012), thus leading to the observed cognitive impairment in Tm4sf2 knockout mice (Murru et al, 2017, 2021). The results of the current study propose that TSPAN7 interacts with both β3 integrin and RANK in osteoclasts.…”

Integrin β1/FAK/SRC signal pathway is involved in autism spectrum disorder inTspan7knockout rats

“…Previous studies found that TSPAN7 was involved in spine maturation in cultured hippocampal neurons through a direct interaction with PICK1 ( Bassani et al, 2012 ). Tspan7 knockout caused an ASD-related phenotype in mice, and the deletion of TSPAN7 altered voltage-gated ion channels function and decreased PKC-ERK signaling ( Murru et al, 2021 ). Synaptic dysfunction had been revealed to be a hallmark of ASD ( Guang et al, 2018 ).…”

Loss of tetraspanin‐7 expression reduces pancreatic β‐cell exocytosis Ca2+ sensitivity but has limited effect on systemic metabolism

“…Reduced body weight and ad libitum plasma glucose was observed in Tspan7 y/− mice (Figure 2a,b), but this was not linked to changes in plasma insulin (measured as insulin and C‐peptide, Figure 2c,d). These effects may instead be attributable to the neurological manifestations of Tspan7 ablation, including depressive behaviour 23 . We observed no change in circulating proinsulin levels (Figure 2e), suggesting normal insulin processing in Tspan7 y/− β‐cells.…”