Presynaptic targeting of alpha4beta 2 nicotinic acetylcholine receptors is regulated by neurexin-1beta.
ABSTRACT The mechanisms involved in the targeting of neuronal nicotinic acetylcholine receptors (AChRs), critical for their functional organization at neuronal synapses, are not well understood. We have identified a novel functional association between alpha4beta2 AChRs and the presynaptic cell adhesion molecule, neurexin-1beta. In non-neuronal tsA 201 cells, recombinant neurexin-1beta and mature alpha4beta2 AChRs form complexes. alpha4beta2 AChRs and neurexin-1beta also coimmunoprecipitate from rat brain lysates. When exogenous alpha4beta2 AChRs and neurexin-1beta are coexpressed in hippocampal neurons, they are robustly targeted to hemi-synapses formed between these neurons and cocultured tsA 201 cells expressing neuroligin-1, a postsynaptic binding partner of neurexin-1beta. The extent of synaptic targeting is significantly reduced in similar experiments using a mutant neurexin-1beta lacking the extracellular domain. Additionally, when alpha4beta2 AChRs, alpha7 AChRs, and neurexin-1beta are coexpressed in the same neuron, only the alpha4beta2 AChR colocalizes with neurexin-1beta at presynaptic terminals. Collectively, these data suggest that neurexin-1beta targets alpha4beta2 AChRs to presynaptic terminals, which mature by trans-synaptic interactions between neurexins and neuroligins. Interestingly, human neurexin-1 gene dysfunctions have been implicated in nicotine dependence and in autism spectrum disorders. Our results provide novel insights as to possible mechanisms by which dysfunctional neurexins, through downstream effects on alpha4beta2 AChRs, may contribute to the etiology of these neurological disorders.
- SourceAvailable from: Elena Orekhova[Show abstract] [Hide abstract]
ABSTRACT: The extended phenotype of autism spectrum disorders (ASD) includes a combination of arousal regulation problems, sensory modulation difficulties, and attention re-orienting deficit. A slow and inefficient re-orienting to stimuli that appear outside of the attended sensory stream is thought to be especially detrimental for social functioning. Event-related potentials (ERPs) and magnetic fields (ERFs) may help to reveal which processing stages underlying brain response to unattended but salient sensory event are affected in individuals with ASD. Previous research focusing on two sequential stages of the brain response-automatic detection of physical changes in auditory stream, indexed by mismatch negativity (MMN), and evaluation of stimulus novelty, indexed by P3a component,-found in individuals with ASD either increased, decreased, or normal processing of deviance and novelty. The review examines these apparently conflicting results, notes gaps in previous findings, and suggests a potentially unifying hypothesis relating the dampened responses to unattended sensory events to the deficit in rapid arousal process. Specifically, "sensory gating" studies focused on pre-attentive arousal consistently demonstrated that brain response to unattended and temporally novel sound in ASD is already affected at around 100 ms after stimulus onset. We hypothesize that abnormalities in nicotinic cholinergic arousal pathways, previously reported in individuals with ASD, may contribute to these ERP/ERF aberrations and result in attention re-orienting deficit. Such cholinergic dysfunction may be present in individuals with ASD early in life and can influence both sensory processing and attention re-orienting behavior. Identification of early neurophysiological biomarkers for cholinergic deficit would help to detect infants "at risk" who can potentially benefit from particular types of therapies or interventions.Frontiers in Human Neuroscience 01/2014; 8:34. · 2.90 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABAB receptor (GABABR)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABABR, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABABR. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABABR with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABAAR with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABABR and postsynaptic GABAAR. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABAAR and GABABR subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors.Proceedings of the National Academy of Sciences 03/2014; · 9.81 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The involvement of the cholinergic system in learning, memory and attention has long been recognized, although its neurobiological mechanisms are not fully understood. Recent evidence identifies the endogenous cholinergic signaling via nicotinic acetylcholine receptors (nAChRs) as key players in determining the morphological and functional maturation of the glutamatergic system. Here, we review the available experimental and clinical evidence of nAChRs contribution to the establishment of the glutamatergic system, and therefore to cognitive function. We provide some clues of the putative underlying molecular mechanisms and discuss recent human studies that associate genetic variability of the genes encoding nAChR subunits with cognitive disorders. Finally, we discuss the new avenues to therapeutically targeting nAChRs in persons with cognitive dysfunction for which the α7-nAChR subunit is an important etiological mechanism.Neuroscience & Biobehavioral Reviews 05/2014; · 10.28 Impact Factor