MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

García‐Osta, Ana; Tsokas, Panayiotis; Pollonini, Gabriella; Landau, Emmanuel M.; Blitzer, Robert D.; Alberini, Cristina M.

doi:10.1523/jneurosci.1674-06.2006

Cited by 87 publications

(89 citation statements)

References 74 publications

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“…1A). An unpaired (UP) control group was exposed to the IA context and received the footshock, but these two experiences were separated by 1 h and were therefore unpaired, preventing IA learning (Garcia-Osta et al 2006). Immunoblot analysis using MMP-9-specific antisera that recognize both proand active-forms shows that IA training induces a gradual and transient increase in levels of both forms of MMP-9 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Animals were returned to their home cages for 1 h, then brought back and footshocked directly (2 sec, 0.65 mA), without further exploration. Previous studies have shown that such UP controls fail to form IA memory or display IA training-induced changes in expression of certain genes (Garcia-Osta et al 2006). After footshock, UP control rats were returned to their home cages and were sacrificed at 24 or 48 h post-shock.…”

Section: Inhibitory Avoidance Taskmentioning

confidence: 99%

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The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory

Nagy¹,

Bozdagi²,

Huntley³

2007

Learn. Mem.

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Matrix metalloproteinases (MMPs) are a family of extracellularly acting proteolytic enzymes with well-recognized roles in plasticity and remodeling of synaptic circuits during brain development and following brain injury. However, it is now becoming increasingly apparent that MMPs also function in normal, nonpathological synaptic plasticity of the kind that may underlie learning and memory. Here, we extend this idea by investigating the role and regulation of MMP-9 in an inhibitory avoidance (IA) learning and memory task. We demonstrate that following IA training, protein levels and proteolytic activity of MMP-9 become elevated in hippocampus by 6 h, peak at 12-24 h, then decline to baseline values by ∼72 h. When MMP function is abrogated by intrahippocampal infusion of a potent gelatinase (MMP-2 and MMP-9) inhibitor 3.5 h following IA training, a time prior to the onset of training-induced elevation in levels, IA memory retention is significantly diminished when tested 1-3 d later. Animals impaired at 3 d exhibit robust IA memory when retrained, suggesting that such impairment is not likely attributed to toxic or other deleterious effects that permanently disrupt hippocampal function. In anesthetized adult rats, the effective distance over which synaptic plasticity is impaired by a single intrahippocampal infusion of the MMP inhibitor of the kind that blocks IA memory is ∼1200 µm. Taken together, these data suggest that IA training induces a slowly emerging, but subsequently protracted period of MMP-mediated proteolysis critical for enabling long-lasting synaptic modification that underlies long-term memory consolidation.New information is learned and remembered through functional and structural modifications of synaptic connections (Bliss and Collingridge 1993;Rogan et al. 1997;Rioult-Pedotti et al. 1998Jorntell and Hansel 2006;Pastalkova et al. 2006;Whitlock et al. 2006). Several kinds of learning and memory tasks have been shown to drive changes in neurotransmitter receptor function and/or localization (Cammarota et al. 1995;Bevilaqua et al. 2005;Rumpel et al. 2005;Whitlock et al. 2006), as well as induce over time changes in synapse number or morphology (O'Malley et al. 2000;Geinisman et al. 2001;Eyre et al. 2003;Leuner et al. 2003;Maviel et al. 2004;Lamprecht et al. 2006;Rekart et al. 2007). These observations suggest that there must be learninginduced cellular mechanisms for coordinating functional and structural remodeling of synaptic connectivity to enable longterm memory, but there is little known about the molecules that could fulfill such a role.Learning-related, regulated extracellular proteolysis could be one mechanism for coordinating functional and structural synaptic plasticity, thereby enabling memory (Huang et al. 1996;Madani et al. 1999;Calabresi et al. 2000;Pawlak et al. 2002;Tamura et al. 2006). It is well-recognized that extracellular matrix (ECM) proteins as well synaptic cell adhesion molecules contribute to both functional and structural aspects of synaptic plasticity, are modified by l...

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Section: Resultsmentioning

confidence: 99%

Section: Inhibitory Avoidance Taskmentioning

confidence: 99%

The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory

Nagy¹,

Bozdagi²,

Huntley³

2007

Learn. Mem.

View full text Add to dashboard Cite

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“…Using Northern blot analysis, MuSK is not detected in rat brain (Valenzuela et al, 1995). In contrast, transcripts for MuSK were found in the brain of other species (Ganju et al, 1995;Fu et al, 1999;Garcia-Osta et al, 2006). Because agrin signaling in the brain might be mediated by MuSK, we looked at the expression of MuSK on the mRNA and protein level.…”

Section: The Receptor Tyrosine Kinase Musk Is Localized To Cns Synapsesmentioning

confidence: 94%

Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death

Ksiazek¹,

Burkhardt²,

Lin³

et al. 2007

J. Neurosci.

107

111

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Agrin-deficient mice die at birth because of aberrant development of the neuromuscular junctions. Here, we examined the role of agrin at brain synapses. We show that agrin is associated with excitatory but not inhibitory synapses in the cerebral cortex. Most importantly, we examined the brains of agrin-deficient mice whose perinatal death was prevented by the selective expression of agrin in motor neurons. We find that the number of presynaptic and postsynaptic specializations is strongly reduced in the cortex of 5-to 7-week-old mice. Consistent with a reduction in the number of synapses, the frequency of miniature postsynaptic currents was greatly decreased. In accordance with the synaptic localization of agrin to excitatory synapses, changes in the frequency were only detected for excitatory but not inhibitory synapses. Moreover, we find that the muscle-specific receptor tyrosine kinase MuSK, which is known to be an essential component of agrin-induced signaling at the neuromuscular junction, is also localized to a subset of excitatory synapses. Finally, some components of the mitogen-activated protein (MAP) kinase pathway, which has been shown to be activated by agrin in cultured neurons, are deregulated in agrin-deficient mice. In summary, our results provide strong evidence that agrin plays an important role in the formation and/or the maintenance of excitatory synapses in the brain, and we provide evidence that this function involves MAP kinase signaling.

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“…No effects were observed with the presentation of scrambled OGNs to either type of neuron. In another study (Garcia-Osta et al, 2006), intracerebral delivery of antisense OGN for a brain-expressed and muscle-specific tyrosine kinase receptor (MuSK) disrupted the ability of the local hippocampal network to generate theta activity in vitro. These results suggest that specific protein products of a neuron are a vital part of its ability to function on its own and within a network; inhibiting just one product can have devastating effects on electrical activity and responsiveness.…”

Section: Is Protein Synthesis Necessary For Neural Activity?mentioning

confidence: 99%

Neurosilence: Profound Suppression of Neural Activity following Intracerebral Administration of the Protein Synthesis Inhibitor Anisomycin

Sharma¹,

Nargang²,

Dickson³

2012

J. Neurosci.

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Early in their formation, memories are thought to be labile, requiring a process called consolidation to give them near-permanent stability. Evidence for consolidation as an active and biologically separate mnemonic process has been established through posttraining manipulations of the brain that promote or disrupt subsequent retrieval. Consolidation is thought to be ultimately mediated via protein synthesis since translational inhibitors such as anisomycin disrupt subsequent memory when administered in a critical time window just following initial learning. However, when applied intracerebrally, they may induce additional neural disturbances. Here, we report that intrahippocampal microinfusions of anisomycin in urethane-anesthetized rats at dosages previously used in memory consolidation studies strongly suppressed (and in some cases abolished) spontaneous and evoked local field potentials (and associated extracellular current flow) as well as multiunit activity. These effects were not coupled to the production of pathological electrographic activity nor were they due to cell death. However, the amount of suppression was correlated with the degree of protein synthesis inhibition as measured by autoradiography and was also observed with cycloheximide, another translational inhibitor. Our results suggest that (1) the amnestic effects of protein synthesis inhibitors are confounded by neural silencing and that (2) intact protein synthesis is crucial for neural signaling itself.

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MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

Cited by 87 publications

References 74 publications

The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory

The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory

Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death

Neurosilence: Profound Suppression of Neural Activity following Intracerebral Administration of the Protein Synthesis Inhibitor Anisomycin

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