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

Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2006; 26(30):7919-32. DOI: 10.1523/JNEUROSCI.1674-06.2006
Source: PubMed


Muscle-specific tyrosine kinase receptor (MuSK) has been believed to be mainly expressed and functional in muscle, in which it mediates the formation of neuromuscular junctions. Here we show that MuSK is expressed in the brain, particularly in neurons, as well as in non-neuronal tissues. We also provide evidence that MuSK expression in the hippocampus is required for memory consolidation, because temporally restricted knockdown after training impairs memory retention. Hippocampal disruption of MuSK also prevents the learning-dependent induction of both cAMP response element binding protein (CREB) phosphorylation and CCAAT enhancer binding protein beta (C/EBPbeta) expression, suggesting that the role of MuSK during memory consolidation critically involves the CREB-C/EBP pathway. Furthermore, we found that MuSK also plays an important role in mediating hippocampal oscillatory activity in the theta frequency as well as in the induction and maintenance of long-term potentiation, two synaptic responses that correlate with memory formation. We conclude that MuSK plays an important role in brain functions, including memory formation. Therefore, its expression and role are broader than what was believed previously.

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    • "Considering this fact, Huang and Kandel (2006) used the terms 'weak L-LTP' (not to be confused with 'weak LTP' considered to be E-LTP, LTP1 or LTP induced by weak protocols) to differentiate it from 'strong L-LTP' when the effect of manipulation was partial. Although the functional significance of this attenuated, but not completely erased, LTP has not been taken in consideration in protein synthesis inhibitor studies, there are several lines of evidence that confirm some correlation between the impaired or enhanced LTP and learning deficit or improvement, respectively (e.g., Laroche et al., 1989; Maren et al., 1994; Manabe et al., 1998, 2000; Malleret et al., 2001; Zeng et al., 2001; Schulz et al., 2002, 2004; Chan et al., 2003; Garcia-Osta et al., 2006), regardless of its duration. However, in an interesting paper by Lisman et al. (2005) the authors pointed out that LTP magnitude was not always indicative of LTP vulnerability to various inhibitors. "
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    ABSTRACT: Long-term potentiation (LTP) remains the most widely accepted model for learning and memory. In accordance with this belief, the temporal differentiation of LTP into early and late phases is accepted as reflecting the differentiation of short-term and long-term memory. Moreover, during the past 30 years, protein synthesis inhibitors have been used to separate the early, protein synthesis-independent (E-LTP) phase and the late, protein synthesis-dependent (L-LTP) phase. However, the role of these proteins has not been formally identified. Additionally, several reports failed to show an effect of protein synthesis inhibitors on LTP. In this review, a detailed analysis of extensive behavioral and electrophysiological data reveals that the presumed correspondence of LTP temporal phases to memory phases is neither experimentally nor theoretically consistent. Moreover, an overview of the time courses of E-LTP in hippocampal slices reveals a wide variability ranging from <1 h to more than 5 h. The existence of all these conflictual findings should lead to a new vision of LTP. We believe that the E-LTP vs. L-LTP distinction, established with protein synthesis inhibitor studies, reflects a false dichotomy. We suggest that the duration of LTP and its dependency on protein synthesis are related to the availability of a set of proteins at synapses and not to the de novo synthesis of plasticity-related proteins. This availability is determined by protein turnover kinetics, which is regulated by previous and ongoing electrical activities and by energy store availability.
    Reviews in the neurosciences 05/2015; DOI:10.1515/revneuro-2014-0072 · 3.33 Impact Factor
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    • "Brain nicotinic AChRs, most notably α7 and α3-containing subtypes, have been found to bind antibodies from sera of MG patients [17], and immunization against the ganglionic α3 subunit has been found to produce both muscle and neuronal AChR antibodies [18]. MuSK antibodies known to attack the neuromuscular junction have been recently identified in rat brains where they influence hippocampal oscillatory activity and memory consolidation [19]. "
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    ABSTRACT: In this study we demonstrate that myasthenia gravis, an autoimmune disease strongly identified with deficient acetylcholine receptor transmission at the post-synaptic neuromuscular junction, is accompanied by a profound loss of olfactory function. Twenty-seven MG patients, 27 matched healthy controls, and 11 patients with polymiositis, a disease with peripheral neuromuscular symptoms analogous to myasthenia gravis with no known central nervous system involvement, were tested. All were administered the University of Pennsylvania Smell Identification Test (UPSIT) and the Picture Identification Test (PIT), a test analogous in content and form to the UPSIT designed to control for non-olfactory cognitive confounds. The UPSIT scores of the myasthenia gravis patients were markedly lower than those of the age- and sex-matched normal controls [respective means (SDs) = 20.15 (6.40) & 35.67 (4.95); p<0.0001], as well as those of the polymiositis patients who scored slightly below the normal range [33.30 (1.42); p<0.0001]. The latter finding, along with direct monitoring of the inhalation of the patients during testing, implies that the MG-related olfactory deficit is unlikely due to difficulties sniffing, per se. All PIT scores were within or near the normal range, although subtle deficits were apparent in both the MG and PM patients, conceivably reflecting influences of mild cognitive impairment. No relationships between performance on the UPSIT and thymectomy, time since diagnosis, type of treatment regimen, or the presence or absence of serum anti-nicotinic or muscarinic antibodies were apparent. Our findings suggest that MG influences olfactory function to the same degree as observed in a number of neurodegenerative diseases in which central nervous system cholinergic dysfunction has been documented.
    PLoS ONE 10/2012; 7(10):e45544. DOI:10.1371/journal.pone.0045544 · 3.23 Impact Factor
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    • "Anti- Musk antibodies, other than in neuromuscular junction, were detected in brain both in neurons and nonneuronal tissues. Moreover, MuSK expression in the hippocampus seems to play a critical role in memory retention [19]. According to this finding some patients affected by MG were observed to have memory deficits [20]. "
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    ABSTRACT: Muscle-specific tyrosine kinase- (MuSK-) antibodies-positive Myasthenia Gravis accounts for about one third of Seronegative Myasthenia Gravis and is clinically characterized by early onset of prominent bulbar, neck, shoulder girdle, and respiratory weakness. The response to medical therapy is generally poor. Here we report a case of late-onset MuSK-antibodies-positive Myasthenia Gravis presenting with signs of cognitive impairment and parkinsonism in addition to bulbar involvement and external ophthalmoplegia. The pattern of involvement of both peripheral and central nervous system dysfunction might suggest a common pathogenic mechanism, involving impaired cholinergic transmission.
    Neurology Research International 07/2011; 2011:859802. DOI:10.1155/2011/859802
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