Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2−/y Mice

Abstract

Intellectual disability affects 2–3% of the world's population and typically begins during childhood, causing impairments in social skills and cognitive abilities. Mutations in the TM4SF2 gene, which encodes the TSPAN7 protein, cause a severe form of intellectual disability, and currently, no therapy is able to ameliorate this cognitive impairment. We previously reported that, in cultured neurons, shRNA-mediated down-regulation of TSPAN7 affects AMPAR trafficking by enhancing PICK1–GluA2 interaction, thereby increasing the intracellular retention of AMPAR. Here, we found that loss of TSPAN7 function in mice causes alterations in hippocampal excitatory synapse structure and functionality as well as cognitive impairment. These changes occurred along with alterations in AMPAR expression levels. We also found that interfering with PICK1–GluA2 binding restored synaptic function in Tm4sf2−/y mice. Moreover, potentiation of AMPAR activity via the administration of the ampakine CX516 reverted the neurological phenotype observed in Tm4sf2−/y mice, suggesting that pharmacological modulation of AMPAR may represent a new approach for treating patients affected by TM4SF2 mutations and intellectual disability.

TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering

“…Tetraspanins also bind cholesterol, an interaction thought to mediate their self-association (Charrin et al, 2003a). To date, 33 mammalian tetraspanins have been described to act in cell-cell adhesion, cell motility and proliferation, immunity, and nervous system development (Hemler, 2005), but there is little work on their synaptic function (Bassani et al, 2012;Murru et al, 2017Murru et al, , 2018, thus their supramolecular organization at synapses is unknown.…”

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

“…In accordance, LHb has been reported to be involved in behavioral flexibility ( Baker and Mizumori 2017 ; Mizumori and Baker 2017 ), sociability ( Benekareddy et al 2018 ), learning and memory ( Lecourtier et al 2004 ; Bromberg-Martin et al 2010 ; Shumake et al 2010 ) that are often impaired in ID and ASD patients ( Moretto et al 2018 ). Here, we report that Tm4sf2 −/y mice, beyond an ID-like phenotype ( Murru et al 2017 a), display altered sociability, increased repetitive behaviors, anhedonic- and depressive-like states. Furthermore, we found that LHb neurons of Tm4sf2 −/y mice show reduced excitability, aberrant neuronal firing pattern and altered sodium and potassium voltage-gated ion channels function.…”

“…Coronal slices (thickness, 270 μm) from Tm4sf2 +/y and Tm4sf2 −/y 40–60 days old male mice were prepared as previously described ( Murru et al 2017 ).…”

“…Beyond the role in immune system, cancer progression and metastatic processes, recently tetraspanins gained much attention as synaptic regulators ( Murru et al 2018 ). Indeed, these proteins act as molecular facilitators interacting with other proteins, such as cell adhesion and signaling molecules ( Bassani and Cingolani 2012 ; Termini and Gillette 2017 ; Moretto et al 2019 ), membrane receptors ( Lee et al 2017 ; Murru et al 2017 ), ion channels ( Mallmann et al 2013 ), and with each other ( Charrin et al 2014 ), forming the Tetraspanin Enriched Microdomains (TEMs). In this way, tetraspanins favor the clusterization of membrane protein and their chance of interactions.…”

“…Previously, we demonstrated that TSPAN7 is important for synapse formation and function, identifying protein interacting with C kinase 1 (PICK1) as a direct interactor of TSPAN7 ( Bassani et al 2012 ). Recently, using a knockout mouse model for Tm4sf2 (Tm4sf2 −/y ), we found that TSPAN7 plays a key role in hippocampal excitatory synapse formation, function and plasticity as well as in learning and memory ( Murru et al 2017 ).…”