Abstract
Foxp2(R552H) knock-in (KI) mouse pups with a mutation related to human speech–language disorders exhibit poor development of cerebellar Purkinje cells and impaired ultrasonic vocalization (USV), a communication tool for mother-offspring interactions. Thus, human speech and mouse USV appear to have a Foxp2-mediated common molecular basis in the cerebellum. Mutations in the gene encoding the synaptic adhesion molecule CADM1 (RA175/Necl2/SynCAM1/Cadm1) have been identified in people with autism spectrum disorder (ASD) who have impaired speech and language. In the present study, we show that both Cadm1-deficient knockout (KO) pups and Foxp2(R552H) KI pups exhibit impaired USV and smaller cerebellums. Cadm1 was preferentially localized to the apical–distal portion of the dendritic arbor of Purkinje cells in the molecular layer of wild-type pups, and VGluT1 level decreased in the cerebellum of Cadm1 KO mice. In addition, we detected reduced immunoreactivity of Cadm1 and VGluT1 on the poorly developed dendritic arbor of Purkinje cells in the Foxp2(R552H) KI pups. However, Cadm1 mRNA expression was not altered in the Foxp2(R552H) KI pups. These results suggest that although the Foxp2 transcription factor does not target Cadm1, Cadm1 at the synapses of Purkinje cells and parallel fibers is necessary for USV function. The loss of Cadm1-expressing synapses on the dendrites of Purkinje cells may be associated with the USV impairment that Cadm1 KO and Foxp2(R552H) KI mice exhibit.
Highlights
Cadm1, a member of the immunoglobulin superfamily (IgSF), localizes to both sides of the synaptic cleft and functions as a synaptic cell–cell adhesion molecule
We examined the localization of Cadm1 in the cerebellum of Foxp2(R552H) KI mice and found that Foxp2(R552H) KI pups (P11) had poorly developed Purkinje cell dendrites with reduced immunoreactivity for Synaptophysin [13] (Figure 6)
We found that Cadm1 KO mice had smaller cerebellums, poor development of dendrites of Purkinje cells, and impaired ultrasonic vocalization (USV) (Figures 1, 2, 3 and S1), as observed in Foxp2(R552H) KI mouse pups
Summary
Cadm ( known as RA175, Necl, and SynCAM1), a member of the immunoglobulin superfamily (IgSF), localizes to both sides of the synaptic cleft and functions as a synaptic cell–cell adhesion molecule. At the pre-synapse, Cadm associates with calmodulin associated serine/threonine kinase (CASK) via a single PDZ domain [1]. Mutations in genes encoding synaptic adhesion proteins, including neuroligin (NLGN) 3 and 4, contactin-associated protein-like 2 (CNTNAP2, Caspr2), and CADM1, are associated with autism spectrum disorder (ASD) [3,4,5]; the CADM1 mutations H246N and Y251S have been found in people diagnosed with ASD who had impaired social interactions and communication, including speech and language impairments [5]. Cadm knockout (KO) mice [7] exhibit abnormal social and emotional behaviors that share similarities with some behaviors associated with ASD [8]. These findings suggest that CADM1 loss of function may be linked to ASD
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