Deficits in memory and motor performance in synaptotagmin IV mutant mice

Ferguson, Gregory D.; Anagnostaras, Stephan; Silva, Alcino J.; Herschman, Harvey R.

doi:10.1073/pnas.100104597

Cited by 99 publications

(101 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data are consistent with a role for defective endocytosis as an underlying mechanism in HD (Trushina et al, 2006). Importantly, mouse knock-outs of synaptic and/or htt-interacting proteins such as HIP1 (Ferguson et al, 2000;Metzler et al, 2007;Nystuen et al, 2007) often have neurological phenotypes that may be relevant to HD pathogenesis.…”

supporting

confidence: 87%

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Parker¹,

Metzler²,

Georgiou³

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

Huntingtin-interacting protein 1 (HIP1) was identified through its interaction with htt (huntingtin), the Huntington's disease (HD) protein. HIP1 is an endocytic protein that influences transport and function of AMPA and NMDA receptors in the brain. However, little is known about its contribution to neuronal dysfunction in HD.We report that the Caenorhabditis elegans HIP1 homolog hipr-1 modulates presynaptic activity and the abundance of synaptobrevin, a protein involved in synaptic vesicle fusion. Presynaptic function was also altered in hippocampal brain slices of HIP1 Ϫ/Ϫ mice demonstrating delayed recovery from synaptic depression and a reduction in paired-pulse facilitation, a form of presynaptic plasticity. Interestingly, neuronal dysfunction in transgenic nematodes expressing mutant N-terminal huntingtin was specifically enhanced by hipr-1 loss of function. A similar effect was observed with several other mutant proteins that are expressed at the synapse and involved in endocytosis, such as unc-11/AP180, unc-26/synaptojanin, and unc-57/endophilin.Thus, HIP1 is involved in presynaptic nerve terminal activity and modulation of mutant polyglutamine-induced neuronal dysfunction. Moreover, synaptic proteins involved in endocytosis may protect neurons against amino acid homopolymer expansion.

show abstract

supporting

confidence: 87%

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Parker¹,

Metzler²,

Georgiou³

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The predominant expression of Syt IV in astrocytes and its absence from nerve terminals is of great interest because hippocampal-based memory formation has been reported to be impaired in syt4 knockout mice (49). Because glutamate released from astrocytes has been shown to activate extrasynaptic Nmethyl-D-aspartate receptors of hippocampal pyramidal neurons (56) it will be extremely interesting to determine whether this gliotransmission pathway is critical for the induction of processes such as long-term potentiation.…”

Section: Discussionmentioning

confidence: 99%

Synaptotagmin IV regulates glial glutamate release

Zhang

Fukuda

Bockstaele

et al. 2004

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

195

168

View full text Add to dashboard Cite

Calcium-binding synaptotagmins (Syts) are membrane proteins that are conserved from nematode to human. Fifteen Syts (Syts I-XV) have been identified in mammalian species. Syt I has been well studied and is a candidate for the Ca 2؉ -sensor that triggers evoked exocytosis underlying fast synaptic transmission. Whereas the functions of the other Syts are unclear, Syt IV is of particular interest because it is rapidly up-regulated after chronic depolarization or seizures, and because null mutations exhibit deficits in fine motor coordination and hippocampus-dependent memory. Screening Syts I-XIII, which are enriched in brain, we find that Syt IV is located in processes of astroglia in situ. Reduction of Syt IV in astrocytes by RNA interference decreases Ca 2؉ -dependent glutamate release, a gliotransmission pathway that regulates synaptic transmission. Mutants of the C2B domain, the only putative Ca 2؉ -binding domain in Syt IV, act in a dominant-negative fashion over Ca 2؉ -regulated glial glutamate release, but not gliotransmission induced by changes in osmolarity. Because we find that Syt IV is expressed predominantly by astrocytes and is not in the presynaptic terminals of the hippocampus, and because Syt IV knockout mice exhibit hippocampal-based memory deficits, our data raise the intriguing possibility that Syt IV-mediated gliotransmission contributes to hippocampal-based memory.

show abstract

“…Of particular interest is the corresponding preservation of the glutamate receptor subunit GluR1, synaptic vesicle markers, and basal levels of active ERK. Note that GluR1 (Schmitt et al, 2004), the synaptic vesicle protein synaptotagmin IV (Ferguson et al, 2000), and the ERK/ MAPK pathway within hippocampal neurons (Shalin et al, 2004) have been shown to play important roles in memory functions, including fear conditioning. The results described here show that indirect enhancement of endocannabinoid responses protects against excitotoxic hippocampal damage and preserves mechanisms necessary for memory encoding.…”

Section: Discussionmentioning

confidence: 99%

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Karanian¹,

Brown²,

Makriyannis³

et al. 2005

J. Neurosci.

114

109

View full text Add to dashboard Cite

The endocannabinoid system has been suggested to elicit signals that defend against several disease states including excitotoxic brain damage. Besides direct activation with CB 1 receptor agonists, cannabinergic signaling can be modulated through inhibition of endocannabinoid transport and fatty acid amide hydrolase (FAAH), two mechanisms of endocannabinoid inactivation. To test whether the transporter and FAAH can be targeted pharmacologically to modulate survival/repair responses, the transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) and the FAAH inhibitor palmitylsulfonyl fluoride (AM374) were assessed for protection against excitotoxicity in vitro and in vivo. AM374 and AM404 both enhanced mitogen-activated protein kinase (MAPK) activation in cultured hippocampal slices. Interestingly, combining the distinct inhibitors produced additive effects on CB 1 signaling and associated neuroprotection. After an excitotoxic insult in the slices, infusing the AM374/AM404 combination protected against cytoskeletal damage and synaptic decline, and the protection was similar to that produced by the stable CB 1 agonist AM356 (R-methanandamide). AM374/ AM404 and the agonist also elicited cytoskeletal and synaptic protection in vivo when coinjected with excitotoxin into the dorsal hippocampus. Correspondingly, potentiating endocannabinoid responses with the AM374/AM404 combination prevented behavioral alterations and memory impairment that are characteristic of excitotoxic damage. The protective effects mediated by AM374/AM404 were (1) evident 7 d after insult, (2) correlated with the preservation of CB 1 -linked MAPK signaling, and (3) were blocked by a selective CB 1 antagonist. These results indicate that dual modulation of the endocannabinoid system with AM374/AM404 elicits neuroprotection through the CB 1 receptor. The transporter and FAAH are modulatory sites that may be exploited to enhance cannabinergic signaling for therapeutic purposes.

show abstract

Deficits in memory and motor performance in synaptotagmin IV mutant mice

Cited by 99 publications

References 55 publications

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Synaptotagmin IV regulates glial glutamate release

Dual Modulation of Endocannabinoid Transport and Fatty Acid Amide Hydrolase Protects against Excitotoxicity

Contact Info

Product

Resources

About