Trans-interaction of SALM5 and in vivo function of NGL-1

Abstract

Abstract (PART1: Trans-interaction of SALM5) Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs

LAR, PTP, and PTP). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength.

Abstract (PART2: In vivo function of NGL-1) Section 1. Suppressed total neuronal activity in NGL-1 deletion mice produces robust anxiolytic phenotype NGL-1 is a post-synaptic adhesion molecule that interacts with its presynaptic partner, netrin-G1. Although NGL-1 itself does not have a strong genetic correlation with neurodevelopmental disorders, advanced genetic analysis recently revealed its role as a genetic modifier in such disorders. In addition, its binding molecules are highly associated with Rett syndrome, bipolar disorder and schizophrenia. To gain insights of in vivo function of NGL-1, we analyzed behavioral phenotypes of NGL-1 knockout mice. The most prominent phenotypes were hyperactivity and anxiolytic behavior. We further examined the brain regions engaged with abnormal level of anxiety through c-fos staining. In NGL-1 KO mice, neuronal activity measured by c-fos positive cell number after EPM was suppressed. One of these regions, the ventral dentate gyrus, which is known to play important roles in emotional domain, shows increased excitability possibly in homeostatic response to the changes in neuronal activites. Our findings show that the deletion of NGL-1 suppresses neuronal activities of anxiety-associated brain regions, eventually producing robust anxiolytic phenotype.

Section 2. Impaired short-term plasticity and learning and memory in NGL-1 KO mice Synapses have their own unique synaptic code that define their properties. NetrinG ligand-1 (NGL-1) is a postsynaptic adhesion molecule that trans-interacts with Netrin-G. NGL-1 along with its family protein, NGL-2, shows distinct sub-dendritic expression pattern in hippocampal CA1 pyramidal neuron. Although it is known that the deletion of NGL-2 affects only SR synapse while sparing SLM synapses, the roles of NGL-1 in SLM synapses remain unclear. Unlike the layer-specific impact of NGL-2 knockout, the absence of NGL-1 influences both SR and SLM regions. Morphologically, synapse density was decreased in both SR and SLM but electrophysiological property was largely unaffected except the impairment in the short-term plasticity. According to the western blot, the deficiency of NGL-1 led to disruption of sub-laminar distribution of NGL-2, which possibly resulted in changes in SR region. Moreover, degree of influence of NGL-1 on dorsal and ventral CA1 was different

ventral CA1 was more susceptible to NGL-1 deficit. In memory tests, NGL-1 KO mice show deficits in both spatial and working memory. Our finding reveals that NGL-1 functions beyond its enriched layer, influencing short-term plasticity and spine density in both SR and SLM layers.