Nicotinic receptor modulation of neurotransmitter release in the cerebellum

Filippi, Giovanna De; Baldwinson, Tristan; Sher, Emanuele

doi:10.1016/s0079-6123(04)48024-8

Cited by 24 publications

(9 citation statements)

References 62 publications

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“…Finally, a decrease in acetylcholine and its precursor, choline, suggests a disruption of the cholinergic system in the Fmr1-deficient cerebellum (Fig. 7), which plays an essential developmental role in this region (De Filippi et al 2005). In conclusion, the delicate balance between excitatory and inhibitory inputs appears compromised in the mouse model of FXS at this early post-natal stage corresponding to the time-window of synaptogenesis, with direct consequences on neuronal circuits formation development (Akerman and Cline 2007).…”

Section: Fmr1-deficiency Drives Alterations In Neurotransmitters Levelsmentioning

confidence: 98%

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

Davidovic¹,

Navratil²,

Bonaccorso³

et al. 2011

Genome Res.

104

126

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Fragile X syndrome (FXS) is the first cause of inherited intellectual disability, due to the silencing of the X-linked Fragile X Mental Retardation 1 gene encoding the RNA-binding protein FMRP. While extensive studies have focused on the cellular and molecular basis of FXS, neither human Fragile X patients nor the mouse model of FXS-the Fmr1-null mouse-have been profiled systematically at the metabolic and neurochemical level to provide a complementary perspective on the current, yet scattered, knowledge of FXS. Using proton high-resolution magic angle spinning nuclear magnetic resonance ( 1 H HR-MAS NMR)-based metabolic profiling, we have identified a metabolic signature and biomarkers associated with FXS in various brain regions of Fmr1-deficient mice. Our study highlights for the first time that Fmr1 gene inactivation has profound, albeit coordinated consequences in brain metabolism leading to alterations in: (1) neurotransmitter levels, (2) osmoregulation, (3) energy metabolism, and (4) oxidative stress response. To functionally connect Fmr1-deficiency to its metabolic biomarkers, we derived a functional interaction network based on the existing knowledge (literature and databases) and show that the FXS metabolic response is initiated by distinct mRNA targets and proteins interacting with FMRP, and then relayed by numerous regulatory proteins. This novel ''integrated metabolome and interactome mapping'' (iMIM) approach advantageously unifies novel metabolic findings with previously unrelated knowledge and highlights the contribution of novel cellular pathways to the pathophysiology of FXS. These metabolomic and integrative systems biology strategies will contribute to the development of potential drug targets and novel therapeutic interventions, which will eventually benefit FXS patients.[Supplemental material is available for this article.]Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability (ID) and the most commonly identified genetic cause of autism (Chelly et al. 2006;Gecz et al. 2009). FXS affects 1 in 4000 males and 1 in 7000 females world-wide (Hagerman 2008) and is caused by the silencing of the X-linked Fragile X Mental Retardation 1 (FMR1) gene positioned in Xq27.3. In FXS patients, a dynamic mutation increasing abnormally the number of CGG repeats in the first exon of the FMR1 gene leads to their hypermethylation and the subsequent absence of its gene product, FMRP (Penagarikano et al. 2007). Although a monogenic disorder, FXS is a disease of complex etiology accompanied by behavioral (hyperactivity, autism), neurological (susceptibility to epileptic seizures), as well as physical abnormalities (macroorchidism, elongated face, hyperextensible finger joints) (Penagarikano et al. 2007). A mouse model of FXS knock-out (KO) for the murine homolog of FMR1, has been generated, exhibiting learning and behavioral abnormalities that recapitulate the human phenotype (The Dutch-Belgian Fragile X Consortium 1994). The absence of FMRP induces abnormal extra dendritic spines...

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Section: Fmr1-deficiency Drives Alterations In Neurotransmitters Levelsmentioning

confidence: 98%

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

Davidovic¹,

Navratil²,

Bonaccorso³

et al. 2011

Genome Res.

104

126

View full text Add to dashboard Cite

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“…In both human and rats these sites could be involved in transducing effects of ACh and/or choline upon neurotransmitter release and synaptic function De Filippi et al, 2005). Activation of perisynaptic nAChRs could cause increase in excitability or depolarization of AVPNs, whereas stimulation of presynaptic receptors localized on axonal terminals innervating vagal preganglionic neurons could modulate the release of several substances, including release of glutamate and facilitation of glutamatergic neurotransmission, as shown in other CNS sites (Aramakis and Metherate, 1998;Alkondon et al, 2003;Jones and Wonnacott, 2004).…”

Section: Expression Of Nachrs By Identified Avpnsmentioning

confidence: 99%

Airway-related vagal preganglionic neurons express multiple nicotinic acetylcholine receptor subunits

Dehkordi

Balan

et al. 2006

Autonomic Neuroscience

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Nicotine acting centrally increases bronchomotor tone and airway secretion, suggesting that airwayrelated vagal preganglionic neurons (AVPNs) within the rostral nucleus ambiguus (rNA) express nicotinic acetylcholine receptors (nAChRs). In the present study, we examined the three main functionally characterized subtypes of nAChRs in the CNS, the α7 homomeric and α4β2 heteromeric receptors. First, we characterized the expression of these subunits at the message (mRNA) and protein levels in brain tissues taken from the rNA region, the site where AVPNs are located. In addition, double labeling fluorescent immunohistochemistry and confocal laser microscopy were used to define the presence of α7, α4, and β2 nAChRs on AVPNs that were retrogradely labeled with cholera toxin h subunit (CTb), injected into the upper lung lobe (n = 4) or extrathoracic trachea (n = 4). Our results revealed expression of all three studied subunits at mRNA and protein levels within the rNA region. Furthermore, virtually all identified AVPNs innervating intrapulmonary airways express α7 and α4 nAChR subunits. Similarly, a majority of labeled AVPNs projecting to extrathoracic trachea contain α7 and β2 subunits, but less than half of them show detectable α4 nAChR traits. These results suggest that AVPNs express three major nAChR subunits (α7, α4, and β2) that could assemble into functional homologous or heterologous pentameric receptors, mediating fast and sustained nicotinic effects on cholinergic outflow to the airways.

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“…nAChR stimulation facilitates glutamatergic transmission at selected CNS synapses and enhances a synapse selective form of LTP in the amygdala (11). This facilitation is commonly mediated by presynaptic receptors and likely involves regulation of transmitter release, including the release of glutamate (12)(13)(14). nAChRs also regulate the downstream turnover of selected glutamate receptors such as the AMPA receptor GluR1 subunit (15).…”

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confidence: 99%

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

Lin

Vicini

Hsu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In association with NMDA receptors (NMDARs), neuronal α7 nicotinic ACh receptors (nAChRs) have been implicated in neuronal plasticity as well as neurodevelopmental, neurological, and psychiatric disorders. However, the role of presynaptic NMDARs and their interaction with α7 nAChRs in these physiological and pathophysiological events remains unknown. Here we report that axonal α7 nAChRs modulate presynaptic NMDAR expression and structural plasticity of glutamatergic presynaptic boutons during early synaptic development. Chronic inactivation of α7 nAChRs markedly increased cell surface NMDAR expression as well as the number and size of glutamatergic axonal varicosities in cortical cultures. These boutons contained presynaptic NMDARs and α7 nAChRs, and recordings from outside-out pulled patches of enlarged presynaptic boutons identified functional NMDAR-mediated currents. Multiphoton imaging of presynaptic NMDAR-mediated calcium transients demonstrated significantly larger responses in these enlarged boutons, suggesting enhanced presynaptic NMDAR function that could lead to increased glutamate release. Moreover, whole-cell patch clamp showed a significant increase in synaptic charge mediated by NMDAR miniature EPSCs but no alteration in the frequency of AMPAR miniature EPSCs, suggesting the selective enhancement of postsynaptically silent synapses upon inactivation of α7 nAChRs. Taken together, these findings indicate that axonal α7 nAChRs modulate presynaptic NMDAR expression and presynaptic and postsynaptic maturation of glutamatergic synapses, and implicate presynaptic α7 nAChR/NMDAR interactions in synaptic development and plasticity. silent synapse | synaptic development | synaptic plasticity | alpha bungarotoxin | cytisine

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Nicotinic receptor modulation of neurotransmitter release in the cerebellum

Cited by 24 publications

References 62 publications

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

A metabolomic and systems biology perspective on the brain of the Fragile X syndrome mouse model

Airway-related vagal preganglionic neurons express multiple nicotinic acetylcholine receptor subunits

Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons

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