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.
"Possible role of nAChR-α4β2 in P100 generation is also indirectly supported by the animal studies. These studies have shown that modulation of α4β2-nAChR activation in mice does not influence the magnitude of hippocampal P20—the human analog of P50—but affects the amplitude of the component succeeding P20 (hippocampal N40) (Rudnick et al., 2009; Featherstone et al., 2012). There is convincing evidence in the literature that nAChR stimulation mainly affects the attention reorienting network of the right hemisphere. "
[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 02/2014; 8(1):34. DOI:10.3389/fnhum.2014.00034 · 2.99 Impact Factor
"However, the pre-and post-synaptic distribution of a4b2* nAChRs has long been controversial (Albuquerque et al. 2009). Recently, heterologous a4b2* nAChRs have been shown to be localized to the pre-synaptic membrane as well as to somatodendritic compartments, whereas a7 nAChRs are restricted to dendrites (Xu et al. 2006; Cheng et al. 2009). In addition, a4b2* nAChRs are reported to induce the release of excitatory amino acids from synaptosomes (Rousseau et al. 2005). "
[Show abstract][Hide abstract] ABSTRACT: Cholinergic neurons in the CNS are involved in synaptic plasticity and cognition. Both muscarinic and nicotinic acetylcholine receptors (nAChRs) influence plasticity and cognitive function. The mechanism underlying nAChR-induced plasticity, however, has remained elusive. Here, we demonstrate morphological changes in dendritic spines following activation of α4β2* nAChRs, which are expressed on glutamatergic presynaptic termini of cultured hippocampal neurons. Exposure of the neurons to nicotine resulted in a lateral enlargement of spine heads. This was abolished by dihydro-β-erythroidine, an antagonist of α4β2* nAChRs, but not by α-bungarotoxin, an antagonist of α7 nAChRs. Tetanus toxin or a mixture of 2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione, antagonists of NMDA- and AMPA-type glutamate receptors, blocked the nicotine-induced spine remodeling. In addition, nicotine exerted full spine-enlarging response in the postsynaptic neuron whose β2* nAChR expression was knocked down. Finally, pretreatment with nicotine enhanced the Ca(2+) -response of the neurons to glutamate. These data suggest that nicotine influences the activity of glutamatergic neurotransmission through the activation of presynaptic α4β2* nAChRs, resulting in the modulation of spinal architecture and responsiveness. The present findings may represent one of the cellular mechanisms underlying cholinergic tuning of brain function. This article is protected by copyright. All rights reserved.
Journal of Neurochemistry 10/2013; 128(2). DOI:10.1111/jnc.12470 · 4.28 Impact Factor
"We present a rationale as well as results from a single case report that targeting neuronal nicotinic acetylcholine receptors (nAChR) with drugs specific to the a4b2 nAChR subtype is likely to be useful for ASD treatment. This rationale is based on integrating evidence from multiple types of studies, including our own (Cheng et al. 2009), using postmortem, genetic, functional, and molecular neurobiological methodologies showing that the early loss of nAChRs and their functions, caused by mechanisms yet to be identified, may contribute to the etiology of ASDs. "
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.