Neuroligin-Neurexin Interaction

       Experimental results from the past 10 years have revealed that loss of Neuroligin function has a selective reductive effect on inhibitory synapse function indicating that functional inhibitory synapses rely more heavily on neuroligins than do excitatory synapses.^[1] This was an astonishing discovery as Autism Spectrum Disorders (ASDs) have long been attributed to perturbations in the Excitatory/Inhibitory (E/I) synaptic signal ratios within the brain. Knockdown studies have validated that the selective knockdown of NLGNs resulted in a significant imbalance of E/I transmission possibly altering oscillatory rhythms in the brain.^[3][1] As Sudhof et al. point out, a major reason for the difficitulties in understanding cognitive diseases is that they arise from subtle changes in a subset of synapses as opposed to obvious impairment of all synapses in all circuits.^[2] The altered E/I ratios associated with NLGN dysfunction may be an example of such a “subtle change”. Indeed, mice with loss-of function mutations in NLGN4 exhibit deficits in social interactions and communication that are reminiscent of ASDs.^[4] Of particular interest are those NLGN3 mutations like R451C in which mice have the impaired social ability but elevated learning capacity manifestations reminiscent of “savant” syndrome.^[3] In all, seven point mutations, two translocations and four large-scale deletions in the NRXN1 gene were detected in patients with autism.^[2] These mutations however were only found in a small percentage of Autism patients and are occasionally present in non-symptomatic siblings. Thus, these mutations may only increase the chance of autism rather than actually causing it.^[5]

       There are two , α and β. While α-NRXNs are much larger than β-NRXNs, both contain a single LNS (Laminin, NRXN, sex-hormone-binding globulin domains) domain. Extensive alternative splicing at five unique positions generates thousands of NRXN isoforms which likely specify a “code” of interactions at synapses that varies by location and activity of the neuron.^[2] All NRXN isoforms are found on the presynaptic neuron surface and have the same comprised of 14 beta sheets. The alternative splicing only , including sheets 1, 2, 13 & 14 and the lone alpha helix in the LNS domain.^[6]

       The , which bind to the LNS domains of both alpha and beta NRXNs with nanomolar affinity, are that is homologous with acetylcholinesterase (AChE).^[2] Neuroligin-4, which is expressed on the surface of postsynaptic neurons, consists of a twisted . Three intramolecular between residues Cys110-Cys146, Cys306-Cys317, and Cys476-Cys510, stabilize the structure. Neuroligins readily consisting of two neuroligin subunits. 100% of the dimer with the most unique feature being a ().^[5] The , which in Acetylcholinesterase contains the active center and oxyanion hole, is catalytically inactive due to a substitution of Gly for Ser , which is typically part of AChE’s hydrolytic catalytic triad. The (Residues Cys110-Cys146) forms one side of the rim of the central pocket and is a homolog of the lid found in lipases of the α/β-hydrolase fold family. This Cys-Loop blocks the entry of substrate to the central pocket and provides stability to the NLGN structure.^[5]

        through its to the of the NLGN-4 molecule, . The NRXN-NLGN interface is established by both indirect and direct interactions. Indirect interactions include by residues Asp 137, Asn 238, Val 154 and Ile 236 of NRXN-Beta1 and residues Gln 359 and Gly 360 of NLGN-4. between NRXN and NLGN include extensive hydrogen bonding and Van der Waals contacts as well as between residues NRXN-Arg 109 & NLGN-Glu 270 and NRXN-Arg232 & NLGN Asp 351. The vast majority of these interactions are conserved among all neuroligin types.^[5]

       Several (R437C (451 in NLGN 3), G99S, K378R, & V403M) within NLGN have been positively linked with Autism Spectrum Disorders. Although these mutations are remote from the NLGN-NRXN interface, conclusions can be drawn as to their impact on the function of NLGN. , a mutation shown to result in “savant” like attributes in mice, is believed to increase retention of NLGN in the endoplasmic reticulum preventing correct positioning at the cell surface. It could also disrupt a (Asp 388, Asp 486, Glu 434, and Lys 338) through Trp 484, which are believed to be important for processing events. is believed to affect correct folding of the C-terminal domain of NLGN and prevent formation of the functional dimer. The which interacts with the through Van der Waals contacts could disrupt the Cys-loop reducing NLGN structural integrity. These mutations do not entirely disrupt NLGNs interaction with NRXN, but do impact NLGN in the subtle ways from which autism likely arises.^[5]