Mounting evidence indicates that autism spectrum disorders (ASDs) arise from abnormal synapse formation, the specialized junctions through which brain cells communicate with each other. In our central nervous systems, neuronal networks are established through excitatory and inhibitory synapses. Animal models and patient studies support the hypothesis that dysregulation of the balance of neuronal excitation and inhibition (E-I balance) is one of the pathophysiological hallmarks of ASDs, although the molecular mechanisms regulating E-I balance are largely unknown. For proper synapse formation, excitatory and inhibitory synapses rely on interactions between two key families of cell adhesion molecules. The first are neuroligin isoforms (NL1, NL2, NL3 and NL4) which, which localize specifically at excitatory and inhibitory postsynaptic sites, and regulate synaptic function. In contrast, neurexin isoforms (Nrxn1, Nrxn2 and Nrxn3) are localized at presynaptic terminals, and form """"""""trans-synaptic"""""""" protein complexes with postsynaptic NL isoforms. Importantly, mutations and/or deletions of NL1, NL3, NL4 and Nrxn1 are associated with ASDs. Furthermore, mutant mice that mimic the human NL3 autism mutation exhibit abnormal E-I balance and abnormal inhibitory synaptic function. Therefore, understanding the functional roles of Nrxn-NL3 interactions on inhibitory synaptic transmission will have a profound impact on our understanding of the molecular mechanisms underlying ASDs. We propose to study trans-synaptic molecules, NL3, with respect to the formation of functional inhibitory synapses. We will identify which specific Nrxn isoforms interact with NL3 for functional inhibitory synapse formation. The proposed studies will shed light on how ASD-associated trans-synaptic molecules regulate synaptic function and should create the roadmap towards understanding the pathophysiology of ASDs.
Mounting evidence indicates that autism spectrum disorders (ASDs) arise from abnormal development of synapse formation, the specialized junctions through which brain cells communicate with each other. In this proposal, we will elucidate the pathophysiology of ASDs by elucidating the molecular mechanisms that regulate the formation of functional synapses.
|Mao, Wenjie; Salzberg, Anna C; Uchigashima, Motokazu et al. (2018) Activity-Induced Regulation of Synaptic Strength through the Chromatin Reader L3mbtl1. Cell Rep 23:3209-3222|
|Tzeng, Te-Chen; Hasegawa, Yuto; Iguchi, Risa et al. (2018) Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice. Proc Natl Acad Sci U S A 115:9002-9007|
|Tsantoulas, Christoforos; Denk, Franziska; Signore, Massimo et al. (2018) Mice lacking Kcns1 in peripheral neurons show increased basal and neuropathic pain sensitivity. Pain 159:1641-1651|
|Hasegawa, Yuto; Mao, Wenjie; Saha, Sucharita et al. (2017) Luciferase shRNA Presents off-Target Effects on Voltage-Gated Ion Channels in Mouse Hippocampal Pyramidal Neurons. eNeuro 4:|
|Mao, Wenjie; Watanabe, Takuya; Cho, Sukhee et al. (2015) Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur J Neurosci 41:1025-35|