Figure 5.

MuSK plays a critical role in cholinergic oscillatory activity and long-term potentiation in the CA3–CA1 synapse. A, Left, Carbachol perfusion (50 μm) induced periodic bursts (top) recorded extracellularly in area CA1 of slices from S-ODN-injected hippocampi. Representative experiment of six. Expanded traces (bottom) show that each burst consisted of a series of field events, occurring at ∼10 Hz. Right, Hippocampal M-ODN injection disrupted cholinergic field oscillatory responses in the CA3–CA1 synapse, resulting in regularly spaced unitary events (top). Representative experiment of six; expanded trace shown below. Calibration: top, 0.2 mV, 60 s; bottom, 0.2 mV, 1 s. B, Summary data from all carbachol experiments. The majority (66.7%) of S-ODN slices displayed periodic bursting activity (left), whereas only 8.3% of the M-ODN slices exhibited such activity. The difference is statistically significant (*p < 0.01). Of those M-ODN slices showing nonbursting periodic responses (right), 54.5% displayed pacemaking (PACE) activity, with the remainder showing little or no such activity. Carbachol elicited pacemaking activity in only 11.1% of the S-ODN slices (right). INACT, Inactivity. C, D, Hippocampal M-ODN injection did not affect basal synaptic function. C, Input/output curve of M-ODN-treated slices was indistinguishable from that obtained from S-ODN-treated slices. D, There was no statistical difference between the degree of paired-pulse facilitation (PPF) produced in S-ODN and M-ODN slices. Data are expressed as mean percentage ± SEM. E, Hippocampal M-ODN injection impaired long-term potentiation induced by two trains of HFS (delivered at t = 0) in area CA1. In slices from hippocampi injected with S-ODN, HFS induced stable LTP that persisted for at least 2 h (filled circles). However, injection with M-ODN impaired LTP as early as 5–15 min post-HFS (for fEPSP slope measured over the 5–15 post-HFS period and normalized to baseline, S-ODN vs M-ODN, p < 0.01). After this period, LTP continued to decay in the M-ODN-treated slices relative to controls. The dashed line represents the normalized baseline value of 100%. Inset traces show superimposed sample fEPSPs recorded during the baseline period and 2 h after HFS in S-ODN-treated slices (left traces) or M-ODN-treated slices (right traces). Error bars represent SE. Calibration: 0.5 mV, 10 ms. F, Treatment with M-ODN did not affect the field potential evoked by HFS. Left, Slices were stimulated with two trains of HFS in the presence of 50 μm d-APV, and a second pair of trains was delivered 30 min after APV washout. The field potentials recorded during the second train from each set are shown here. Note the additional field negativity that was observed in the absence of APV, representing the NMDAR-mediated component of the field potential. Right, The AUCs for the potentials obtained in the presence and absence of APV were determined, and the NMDAR-mediated component was calculated by subtracting the +APV AUC from the −APV AUC (total AUC). Treatment with M-ODN affected neither the total AUC nor the NMDAR-mediated component. Calibration: 1 mV, 200 ms.