Related Experiment Video
Updated: Nov 29, 2025
Immunohistochemical Visualization of Hippocampal Neuron Activity After Spatial Learning in a Mouse Model of Neurodevelopmental Disorders
Published on: May 12, 2015
Lateral habenula dysfunctions in Tm4sf2-/y mice model for neurodevelopmental disorder
Luca Murru1, Luisa Ponzoni2, Anna Longatti3
1Institute of Neuroscience, CNR, Milan 20129, Italy; NeuroMI Milan Center for Neuroscience, Università Milano-Bicocca, Milan 20126, Italy.
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.
Insights
Mutations in the TM4SF2 gene cause intellectual disability (ID) and autism spectrum disorder (ASD). Tm4sf2 knockout mice exhibit ID-like traits and altered lateral habenula (LHb) neuronal function, suggesting a role in disease pathophysiology.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Mutations in the TM4SF2 gene, encoding TSPAN7, are linked to severe intellectual disability (ID) and autism spectrum disorder (ASD).
- Previous research indicated TM4SF2 loss impacts cognitive function in mice.
Purpose of the Study:
- To investigate the behavioral and neurophysiological consequences of TM4SF2 loss in mice.
- To explore the role of the lateral habenula (LHb) in the pathophysiology of TM4SF2-related disorders.
Main Methods:
- Generation and characterization of Tm4sf2 knockout (Tm4sf2-/y) mice.
- Behavioral assays assessing sociability, repetitive behaviors, and anhedonia.
- Electrophysiological recordings of LHb neurons to analyze neuronal excitability and firing patterns.
- Investigation of voltage-gated ion channel function and associated signaling pathways (PKC-ERK).
Main Results:
- Tm4sf2-/y mice displayed ID-like phenotypes, reduced sociability, increased repetitive behaviors, and depressive-like states.
- LHb neurons in Tm4sf2-/y mice exhibited hypoexcitability, aberrant firing, and altered sodium/potassium channel function.
- Reduced voltage-gated sodium channel expression and hyperactivity of the PKC-ERK pathway were observed in the LHb.
Conclusions:
- Tm4sf2-/y mice serve as a valuable model for studying ID and ASD-like symptoms.
- Functional alterations in the LHb may contribute to the pathophysiology of TM4SF2-related neurodevelopmental disorders.
More Related Videos
07:03Evaluation of Hemisphere Lateralization with Bilateral Local Field Potential Recording in Secondary Motor Cortex of Mice
Published on: July 31, 2019
10:02Assessment of Spontaneous Alternation, Novel Object Recognition and Limb Clasping in Transgenic Mouse Models of Amyloid-β and Tau Neuropathology
Published on: May 28, 2017