Exploring L1 syndrome-causing L1CAM as a trans-synaptic modulator of mGluR5

Abstract

Neurotransmission typically occurs when neurotransmitters, released by the presynapse, interact with receptors on the postsynapse. Interruptions in these interactions can lead to neurological disorders. Recently, these trans-synaptic interactions were found to involve synaptic adhesion molecules, modulating the activity of a subgroup of G protein-coupled receptors (GPCRs) known as the metabotropic glutamate receptors (mGluRs). A synaptic adhesion molecule called L1CAM has been found to interact with mGluR5. L1CAM is of particular interest because it is the known cause of L1 syndrome, a neurodevelopmental disorder that can cause hydrocephalus, spastic paraplegia, and intellectual disability. As a well-established drug target for neurological disorders, mGluR5, in complex with L1CAM, may have major implications in the etiology of L1 syndrome. We hypothesize that L1CAM is a trans-synaptic modulator of mGluR5. Co-immunoprecipitation experiments were conducted to detect binding of L1CAM, the synaptic adhesion molecule, to the receptors, mGluR5 and mGluR2 (a negative control), at the protein level. Trans-cellular signaling experiments were conducted to determine the functional response of the L1CAM-mGluR interaction at the cellular level. As a result, we found that L1CAM does complex with mGluR5 and not mGluR2. A functional response has not yet been seen, but it is possible that different experimental conditions are required to accurately reflect cell conditions in vivo. In future research, discovery of L1CAM-mGluR5 trans-cellular modulation would lead to further understanding of trans-synaptic interactions between mGluRs and synaptic adhesion molecules, and possibly further the understanding of the etiology of L1 syndrome. As an overarching objective of possible L1CAM-mGluR5 modulation, a therapeutic could be developed to rescue the interaction of L1CAM and mGluR5 in those with L1 syndrome.