Loss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of gamma-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.
Neuroligins are postsynaptic adhesion proteins involved in the establishment of functional synapses in the central nervous system In rodents four genes give rise to neuroligins that function at distinct synapses with corresponding neurotransmitter and subtype specificities In the present study we examined the interactions between the different neuroligins by isolating endogenous oligomeric complexes using in situ cross-linking on primary neurons Examining hippocampal striatal cerebellar and spinal cord cultures we found that neuroligins form constitutive dimers including homomers and most notably neuroligin 1/3 heteromers Additionally we found that neuroligin monomers are specifically retained in the secretory pathway through a cellular quality control mechanism that involves the neuroligin transmembrane domain ensuring that dimerization occurs prior to cell surface trafficking Lastly we identified differences in the dimerization capacity of autism-associated neuroligin mutants and found that neuroligin 3 R471C mutants can form heterodimers with neuroligin 1 The pervasive nature of neuroligin dimerization indicates that the unit of neuroligin function is the dimer and raises intriguing possibilities of distinct heterodimer functions and of interactions between native and mutant neuroligins contributing to disease phenotypes.
