Human Sex-Specific Synaptic Adhesion Proteins NLGN4X and NLGN4Y Regulate the Dual Innervation of Dendritic Spines
Proper function of the human brain requires the correct formation, maturation, and function of a diverse array of synapses. Formation and maturation of a synapse is believed to be induced by interactions between a vast selection of transsynaptic cell adhesion molecules. Deficits in synapse number or synaptic function have been linked to a wide number of neurological and neuropsychiatric disorders. Many of these disorders, termed synaptophathies, show significant sexual dimorphism in the incidence, age of onset, disease severity, and treatment response. The cause of most of these differences between males and females, whether environmental or intrinsic, remains unknown. To investigate the sexual dimorphism of these synaptopathies, we asked whether any of the transsynaptic cell adhesion molecules critical for synapse formation and function are located on the sex chromosomes and, are therefore sex-specific. In humans, the synaptic cell adhesion molecule Neuroligin 4 has not only been identified as sex-specific, residing on the X and the Y chromosomes, but mutations in Neuroligin 4 are also highly penetrant in individuals and families with Autism Spectrum Disorder, a synaptopathy four times more common in males than females that is characterized by alterations to the excitation to inhibition balance in the brain. Yet the role of Neuroligin 4 at the human synapse remains less well understood than the other members of the Neuroligin family. Here I will show that the human, sex-specific Neuroligin 4X and Neuroligin 4Y are expressed in human brain and localize to the postsynaptic density, and I will address a novel function for Neuroligin 4X and Neuroligin 4Y in the regulation of dually innervated dendritic spines, which are implicated in maintaining the excitation to inhibition ratio. I will also show that Neuroligin 4 is involved in inhibitory synaptogenesis and that this synaptogenic ability is modulated by a single amino acid located in the NLGN4X extracellular domain. These studies shed light on a previously unknown function of Neuroligin 4 and their modulation of a class of synapse that has been underappreciated.
Hodge, Rachel, "Human Sex-Specific Synaptic Adhesion Proteins NLGN4X and NLGN4Y Regulate the Dual Innervation of Dendritic Spines" (2021). ETD Collection for Thomas Jefferson University. AAI28869124.