The neural cell adhesion molecule 2 (NCAM2) promotes excitatory synapse formation through increasing insulin and insulin-like growth factor 1 receptor signaling

Deletions in the gene coding for the neural cell adhesion molecule 2 (NCAM2) have been found in patients with intellectual disability. Growing evidence indicates that deficits in synaptogenesis and impaired signaling mediated by the insulin receptor and insulin-like growth factor 1 (IGF1) receptors underlies the pathogenesis of intellectual disability. NCAM2 is enriched at excitatory synapses and is involved in synapse maturation and maintenance. The role of NCAM2 in the regulation of synaptogenesis, however, remains poorly understood. We hypothesized that NCAM2 promotes synaptogenesis through regulating insulin and IGF1 receptor signaling. This thesis demonstrates that in hippocampal neurons, NCAM2 is co-expressed with the insulin and IGF1 receptors during the peak period of synaptogenesis. NCAM2 colocalizes with the active insulin and IGF1 receptors in developing and mature neurons. In NCAM2-deficient neurons and astrocytes, the levels and activity of the insulin and IGF1 receptors are reduced. In addition, the levels of active insulin receptor substrate 1 (IRS1) are reduced in NCAM2-deficient neurons. In transfected CHO cells, NCAM2 increases the levels and activity of the insulin receptor. Further, NCAM2 deficiency affects the levels of the insulin and IGF1 receptors and IRS1 during early postnatal development in the mouse brain. Antibodies against the extracellular domain of NCAM2 trigger a reduction in IGF1 receptor, active insulin/IGF1 receptors and IRS1 levels in cultured hippocampal neurons. In NCAM2-deficient neurons, the ligand-induced loss of the insulin receptor is increased. We show that NCAM2 deficiency impairs synaptogenesis in neurons. In the mouse brain, NCAM2 deficiency disrupts the normal developmental increase in synaptophysin and VGLUT1 levels but does not affect the developmental increase in VGAT levels. Synapse densities are reduced in NCAM2-deficient cultured hippocampal neurons when compared to NCAM2-expressing neurons. In NCAM2-expressing neurons, inhibition of insulin or IGF1 receptor activity reduces the excitatory synapse density but does not affect the inhibitory synapse density. Conversely, in NCAM2-deficient neurons, inhibition of either the insulin or IGF1 receptor does not alter the excitatory synapse density. Collectively, our data indicate that NCAM2 promotes an increase in the levels and activity of the insulin and IGF1 receptors in neurons and thereby promotes synaptogenesis. Aberrations in insulin and IGF1 receptor signaling may contribute to the development of intellectual disability in humans with deletions of the NCAM2 gene.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2026

Author dc:creator

• Zaman, Nishat

• Synapse
• Intellectual disability
• Cell adhesion molecules
• Receptor tyrosine kinases
• NCAM2
• Insulin receptor
• IGF1 receptor
• anzsrc-for: 3101 Biochemistry and cell biology
• anzsrc-for: 310110 Receptors and membrane biology
• anzsrc-for: 320902 Cellular nervous system

Statement dc:rights

• embargoed access
• CC BY 4.0

Licence

• http://purl.org/coar/access_right/c_f1cf
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/32103

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/107176