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,
protein ? (C/EBP?) 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
Muscle-specific tyrosine kinase receptor (MuSK) is a receptor
zuela et al., 1995), mouse (Ganju et al., 1995), Xenopus (Fu et al.,
on Northern blot analyses and in situ hybridizations have re-
tissues of mouse, chicken, and Xenopus (Ganju et al., 1995; Fu et
al., 1999; Ip et al., 2000), it has been generally accepted that this
receptor is mainly expressed and functional only in muscle, in
formation (DeChiara et al., 1996; Sanes and Lichtman, 1999).
Recently, however, MuSK has been reported to also be expressed
in sperm (Kumar et al., 2006).
At the NMJ, MuSK is critically involved in redistributing the
acetylcholine receptors (AChRs) in the postsynaptic apparatus.
form the agrin receptor complex (DeChiara et al., 1996; Sanes
and Lichtman, 1999; Hoch, 2003). In muscle, the activation of
MuSK via the ErbB–neuregulin pathway results in an increase of
AChR expression and triggers the activation of signaling path-
ways that lead to postsynaptic differentiation (Sandrock et al.,
formation and specifically for AChR organization at the NMJs,
because knock-out mice of agrin or MuSK do not form neuro-
muscular synapses, lack AChRs clustering, and die soon after
birth (DeChiara et al., 1996; Gautam et al., 1996). Agrin is ex-
pressed in several tissues, including the CNS, in which it partici-
1995; Ferreira, 1999; Smith and Hilgenberg, 2002). Despite agrin
isoforms with high AChR aggregating activity being widespread
throughout the brain, their receptor complex has not yet been
identified (Smith and Hilgenberg, 2002).
In the brain, synaptogenesis and remodeling of existing syn-
apses are abundant throughout development but also occur in
adulthood after injury and during long-term synaptic plasticity-
associated functions, including memory formation (Scheff et al.,
2005; Waites et al., 2005).
New memories become stable through a process known as
consolidation, which requires the activation of a cascade of gene
expression that critically involves the cAMP response element
binding protein (CREB) and CCAAT enhancer binding protein
(C/EBP) transcription factors (Alberini, 1999) and is accompa-
nied by modifications of synaptic structure and/or number
TheJournalofNeuroscience,July26,2006 • 26(30):7919–7932 • 7919
mitter, hormonal, or neurohumoral systems (Power et al., 2000;
Izquierdo and McGaugh, 2000), which include, among others,
the nicotinic cholinergic system (Gold, 2003; Hogg et al., 2003).
developing and adult tissues other than muscle (Ganju et al.,
CNS (Smith and Hilgenberg, 2002), we investigated the expres-
sion and the functional role of MuSK in the brain.
21- to 28-d-old male Long–Evans rats were used, as specified in Results.
Animals were individually housed and maintained on a 12 h light/dark
All rats were allowed ad libitum access to food and water. All protocols
complied with the National Institutes of Health Guide for the Care and
Use of Laboratory Animals and were approved by the Mt. Sinai School of
Medicine Animal Care Committees.
DNA amplifications. Total RNA was isolated with TRIzol (Invitrogen,
Carlsbad, CA), and reverse transcription was performed using oligo-dT.
Five sets of primers were designed based on the sequence of rat muscle
MuSK (GenBank accession number U34985) and used for PCR amplifi-
cations. Primers were as follows: starting from the 5? end of MuSK se-
quence, forward (F) 1, 5?-TTACAGATGCTCACCCTGGT-3?; reverse
(R) 1, 5?-CTTAATCCAGGACACGGATGG-3?; F2, 5?-CAAGCCATC-
CGTGTCCTGGAT-3?; R2, 5?-ACAGTAGCCTTTGCTTTCTT-3?; F3,
5?-AGTATAGCAGAATGGAGCAA-3?; R3, 5?-GGAAGGCAATGTG-
GTGAGGGT-3?; F4, 5?-CTGCCGAAGGAGGAGAGAGTG-3?; R4, 5?-
GTTTCCATCAGCTTTGTAGTA-3?; F5, 5?-AGGAACATCTACTCCG-
CAGAC-3?; R5, 5?-TGAAAAGATCCTCCTGGGTG-3?. All reactions
were run on an iCycler (Bio-Rad, Hercules, CA) with the following cycle
parameters: 1 cycle of 95°C for 2 min, 40 cycles of 95°C for 30 s followed
used the following: F, 5?-ATGAGAGAGCTCGTCAACAT-3?; R, 5?-
TGAAAAGATCCTCCTGGGTG-3?. Amplification reactions were per-
formed in the iCycler using the following parameters: 1 cycle of 95°C for
sity (New Haven, CT).
Hippocampal neuronal cell culture. Hippocampal neuronal cell cul-
tures (HNCs) were prepared from hippocampi of embryonic day 18
(E18) Long–Evans rats as described previously by Goslin and Banker
(1991) with some modifications. Cells were dissociated by treatment
with 0.25% trypsin for 15 min at 37°C followed by trituration through a
Pasteur pipette. Cells were plated at a density of 1.8 ? 104cells/cm2on
poly-L-lysine-coated coverslips in minimum essential medium (Invitro-
gen; Carlsbad, CA) containing 10% horse serum. After 3 h, when cells
had attached, coverslips were transferred to dishes containing Neuro-
basal medium supplemented with B-27 (Invitrogen), where they were
maintained for the entire time of culture. Cells were used at 12–14 d in
Riboprobe synthesis and in situ hybridization. Three cDNA fragments
rat MuSK (GenBank accession number U34985), subcloned into the
pPCR-Script Amp SK (?) plasmid (Stratagene, La Jolla, CA) were used.
and sense digoxigenin (DIG)-labeled riboprobe synthesis (Roche Diag-
nostics, Indianapolis, IN). Transcription was performed using T3 or T7
polymerases (Roche Diagnostics), and the synthesized riboprobes were
purified with ProbeQuant G-50 Micro Columns (GE Healthcare Bio-
Sciences, Piscataway, NJ). DIG was visualized with anti-DIG antibody
coupled to alkaline phosphatase (AP) and detected with AP Conjugate
paraformaldehyde (PFA) for 30 min at room temperature (RT). Cells
were washed with PBS-diethyl pyrocarbonate (DEPC), permeabilized
ing 0.1% active DEPC. The cells were then equilibrated twice for 10 min
in 2? SSC. Prehybridization was performed at 56°C for 1 h with the
hybridization buffer containing 50% formamide, 5? SSC, 2% blocking
reagent (Roche Diagnostics), and 40 ?g/ml salmon sperm DNA.
Twenty-micrometer rat brain tissue sections were obtained with a cryo-
and postfixed with 4% PFA-DEPC for 15 min at RT. After rinsing with
PBS-DEPC, sections were treated with 0.2 M HCl for 10 min and perme-
abilized with 0.5% Triton X-100 for 10 min at RT. Sections were finally
equilibrated in 0.1 M triethanolamine (TEA) for 5 min and acetylated in
freshly prepared 0.25% acetic anhydrite in 0.1 M TEA for 10 min. Sense
and antisense riboprobes (200 ng/ml for cell cultures and 400 ng/ml for
tissue sections) were diluted in hybridization buffer, denatured at 75°C
for 10 min, and incubated with either HNCs or brain sections overnight
at 56°C. The next day, the samples were rinsed with 2? SSC twice for 10
min at RT, treated with RNase A (20 ?g/ml) for 30 min at 37°C, and
washed sequentially with 2? SSC for 30 min at RT, 2? SSC for 1 h at
65°C, and 0.1? SSC for 1 h at 65°C. After rinsing with Tris-NaCl buffer
(100 mM Tris, 150 mM NaCl), the samples were incubated with blocking
Tris-NaCl buffer] for 30 min at 37°C. The hybridization was detected
using AP-conjugated anti-DIG antibody (Roche Diagnostics) diluted in
at RT. The reaction was revealed by nitroblue tetrazolium/5-bromo-4-
chloro-indolyl-phosphate solution (Roche Diagnostics) diluted in 0.1 M
Tris pH 9.5/0.1 M NaCl containing 1 mM levamisole incubated at RT in
the dark for 3–8 d. Images were acquired with Zeiss (Oberkochen, Ger-
many) Axioscope at the Mount Sinai School of Medicine Microscopy
Shared Resource Facility.
(generously provided by Steven Burden, Skirball Institute of Biomolec-
ular Medicine, New York University, New York, NY) were plated in
six-well plates at 3 ? 105cells per well. Synthetic double-stranded small
interfering RNA (siRNA) targeting MuSK (siRNA-MuSK: sense, 5?
CAGUACUtt) and the nonsilencing siRNA used as negative control
(sense, 5? AGUACUGCUUACGAUACGGtt; antisense, 5? CCGUAU-
CGUAAGCAGUACUtt) were generously provided by Ambion (Austin,
TX). siRNAs were resuspended in RNase-free water at 100 ?M.
HEK293M cells were transfected with Lipofectamine 2000 (Invitrogen)
and siRNAs (200 nM) according to the protocol provided by Invitrogen.
Forty-eight hours after transfection, cells were harvested, lysed, and
analyzed for their MuSK expression levels using quantitative Western
Western blot analysis. Fifty micrograms of total protein extract/lane
were resolved using 7.5% SDS-PAGE and analyzed by Western blot as
incubated in TBS overnight at 4°C. Primary antibodies: goat anti-MuSK
N-terminal (1:300; R&D Systems, Minneapolis, MN), mouse anti-agrin
AGR-520 (1:500; Stressgen, Victoria, CA), rabbit anti-GluR1 (1:2000;
Chemicon Temecula, CA), rabbit anti-C/EBP? (1:10,000; Santa Cruz
Biotechnology, Santa Cruz, CA), rabbit anti-pCREB (1:1000; Upstate
Biotechnology, Lake Placid, NY), rabbit anti-CREB (1:1000; Cell Signal-
ing Technology, Beverly, MA), mouse anti-nuclear pore protein 62
glyceraldehyde 3-phosphate dehydrogenase (GAPDH; 1:4000; Chemi-
con), and mouse anti-actin (1:15 ? 104; Chemicon). Horseradish
peroxidase-coupled specific secondary antibodies (1:4000) were incu-
ECL detection reagents (GE Healthcare Bio-Sciences). Recombinant ex-
tracellular domain of MuSK (R&D Systems) and recombinant insulin-
like growth factor II (IGF-II) (Chemicon) were incubated at 250 ng/ml.
Actin or GAPDH were used for sample normalization and data are ex-
pressed as mean percentage ? SEM of the 0 h? (100%) control mean
values. Statistical analyses were performed as specified in Results. Data
7920 • J.Neurosci.,July26,2006 • 26(30):7919–7932Garcia-Ostaetal.•MuSKExpressionandFunctionintheBrain
coding and representing information integrated at the network
ganize carbachol-induced oscillations, converting the periodic
bursts to single field events that occur at 0.5–1 Hz or, in the case
of MuSK antisense, sometimes producing an almost complete
suppression of field events. Although this similarity suggests that
MuSK might modulate hippocampal nicotinic transmission
through effects on receptor clustering, it is notable that MuSK
recruits phosphotyrosine-binding proteins to regulate transcrip-
Moreover, the cytoplasmic PDZ [postsynaptic density-95 (PSD-
95)/Discs large/zona occludens-1] domain of MuSK suggests the
possibility of a direct interaction with PSD-95, a scaffolding pro-
tein that is critical for the organization and function of the gluta-
matergic synapses whose activation generates theta activity (El-
Husseini et al., 2000; Schnell et al., 2002).
In addition, in vivo MuSK knockdown impaired both induc-
tion and maintenance of hippocampal LTP. These results are in
line with the behavioral experiments and strengthen the conclu-
sion that MuSK plays a role in long-term synaptic plasticity un-
derlying memory formation. The critical role of MuSK during
above, which proposes that MuSK plays an important role that
begins during learning, and is also supported by the observation
that MuSK is required for the activation of the CREB–C/EBP-
dependent cascade. Furthermore, in the context of our behav-
ioral experiments in which MuSK disruption was targeted after
acquisition, the effect of antisense treatment on the maintenance
of LTP is also of particular interest. Indeed, these results confirm
the behavioral data indicating that the integrity of the memory
induction as well as the consolidation process of memory.
In conclusion, based on the results shown in this study, we
propose that hippocampal MuSK mediates learning-induced
synchronization activity, which requires an intact fornix, and is
likely mediated by cholinergic input. This rhythmic activity
would stabilize synaptic plasticity through the activation of the
CREB–C/EBP? pathway. This pathway, which includes MuSK
expression homeostatic regulation, will then lead to memory
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