Multiple Gq-Coupled Receptors Converge on a Common Protein Synthesis-Dependent Long-Term Depression That Is Affected in Fragile X Syndrome Mental Retardation

Volk, Lenora J.; Pfeiffer, Brad E.; Gibson, Jay R.; Huber, Kimberly M.

doi:10.1523/jneurosci.2266-07.2007

Cited by 151 publications

(173 citation statements)

References 75 publications

(154 reference statements)

Supporting

Mentioning

165

Contrasting

Order By: Relevance

“…Startle amplitude and PPI abnormalities, for example, can be linked to dysfunction of modulatory brain regions that are not part of the brainstem startle response circuitry (46), whereas even less is understood about the neural circuitry underlying more complex behaviors such as nesting. Also, and maybe even more importantly, many mice carrying mutations that are linked to a particular disease in human patients exhibit only parts of the disease phenotype, as observed for Rett syndrome, fragile X-syndrome, Alzheimer's disease, and Parkinson's disease mice (39,(47)(48)(49)(50). Needless to say, this problem is particularly challenging for cognitive diseases, because many of their symptoms (e.g., the language disabilities in ASD patients or the hallucinations in schizophrenia patients) cannot even be tested in mice.…”

Section: Discussionmentioning

confidence: 99%

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

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

403

363

View full text Add to dashboard Cite

Deletions in the neurexin-1␣ gene were identified in large-scale unbiased screens for copy-number variations in patients with autism or schizophrenia. To explore the underlying biology, we studied the electrophysiological and behavioral phenotype of mice lacking neurexin-1␣. Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1␣ deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. This defect was specific for excitatory synaptic transmission, because no change in inhibitory synaptic transmission was observed in the hippocampus. Behavioral studies revealed that, compared with littermate control mice, neurexin-1␣ deficient mice displayed a decrease in prepulse inhibition, an increase in grooming behaviors, an impairment in nestbuilding activity, and an improvement in motor learning. However, neurexin-1␣ deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning. Together, these data indicate that the neurexin-1␣ deficiency induces a discrete neural phenotype whose extent correlates, at least in part, with impairments observed in human patients.autism ͉ neuroligin ͉ schizophrenia ͉ synaptic cell-adhesion ͉ synapse N eurexins are neuronal cell-surface proteins that were identified as receptors for ␣-latrotoxin, a presynaptic toxin that triggers massive neurotransmitter release (1-3). Neurexins are largely presynaptic proteins that form a transsynaptic celladhesion complex with postsynaptic neuroligins (4, 5). Vertebrates express three neurexin genes, each of which includes two promoters that direct the synthesis of the longer ␣-neurexins and the shorter ␤-neurexins (6, 7). Neurexins are expressed in all neurons, and are subject to extensive alternative splicing, generating Ͼ1,000 splice variants, some of which exhibit highly regulated developmental and spatial expression patterns (8).The properties of neurexins suggested that they function as synaptic recognition molecules (1), and mediate transsynaptic interactions via binding to neuroligins (4). In support of this overall concept, ␣-neurexin triple KO mice exhibit major impairments in synaptic transmission that manifest largely, but not exclusively, as presynaptic changes (9-13). Importantly, ␣-neurexin KO mice do not display a major decrease in the number of excitatory synapses, and only a moderate decrease in inhibitory synapses (9, 13). Thus, neurexins appear to be essential components of synaptic function whose roles extend to several different components of synapses.In recent years, enormous progress in human genetics has led to the identification of multiple genes that are linked to autism spectrum disorders (ASDs) and schizophrenia. Interestingly, copy-number variations in the neurexin-1␣ gene (but not the neurexin-1␤ gene) were repeatedly observed in patients with ASDs (14 -21) and schizophrenia (22-25). Because 0.5% of all ASD cases appear to harbor neurexin-1␣ gen...

show abstract

Section: Discussionmentioning

confidence: 99%

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

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

403

363

View full text Add to dashboard Cite

show abstract

“…Aberrant signaling in the absence of FMRP was shown to occur through (1) other Gq protein-coupled receptors such as muscarinic acetylcholine receptors (Volk et al, 2007), (2) the dopamine D 1/5 receptors (Wang et al, 2008b(Wang et al, , 2010a, and (3) tyrosine kinase receptor B (TrkB) (Osterweil et al, 2010). Of note, these signaling pathways employ similar molecular mechanisms like mGlu 1/5 -induced LTD. Activation of signaling through both Gq-coupled receptors and dopamine D1 receptors induces protein synthesis-dependent GluA receptor endocytosis (Volk et al, 2007;Wang et al, 2010a). Likewise, TrkB signaling has also been shown to stimulate protein synthesis and regulate GluA receptor surface expression (Caldeira et al, 2007;Minichiello, 2009).…”

Section: Altered Signaling Of Other Membrane Receptorsmentioning

confidence: 99%

“…No serious safety concerns have yet emerged in any of these studies, although only a small population of individuals with FXS has thus far been exposed to mGlu 5 NAMs. It has been proposed that mGlu 1 (Koekkoek et al, 2005) and muscarinic acetylcholine receptor (Volk et al, 2007) NAMs might also be beneficial for individuals with FXS, but these have not been studied. Motor and cognitive side effects were observed in rats exposed to mGlu 1 NAMs (Steckler et al, 2005;Kolasiewicz et al, 2009), raising concerns about the possible toxicity in human trials.…”

Section: Agents Reducing Overactive Signaling Between Receptors and Tmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

show abstract

“…We therefore investigated whether LTD N could be induced by the synaptic activation of muscarinic receptors. We delivered paired-pulse low frequency stimulation (PP-LFS; 200 paired-pulses (50 ms interval) at 1 Hz) 26 , in an attempt to activate the cholinergic fibres present in acute hippocampal slices, and held neurons at -40 mV so that we could simultaneously measure both fast component of EPSC (EPSC F ) and tail component of EPSC (EPSC T ) (Fig. 2a, b).…”

Section: Ltd N Can Be Induced Via the Synaptic Activation Of Machrsmentioning

confidence: 99%

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

et al. 2010

View full text Add to dashboard Cite

Multiple Gq-Coupled Receptors Converge on a Common Protein Synthesis-Dependent Long-Term Depression That Is Affected in Fragile X Syndrome Mental Retardation

Abstract: Gq

Cited by 151 publications

References 75 publications

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95

Contact Info

Product

Resources

About