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.2004 Sep 15;24(37):8153-60.
doi: 10.1523/JNEUROSCI.1766-04.2004.

Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome

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Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome

Alexander M Kleschevnikov et al. J Neurosci..

Abstract

Although many genetic disorders are characterized by cognitive failure during development, there is little insight into the neurobiological basis for the abnormalities. Down syndrome (DS), a disorder caused by the presence of three copies of chromosome 21 (trisomy 21), is characterized by impairments in learning and memory attributable to dysfunction of the hippocampus. We explored the cellular basis for these abnormalities in Ts65Dn mice, a genetic model for DS. Although basal synaptic transmission in the dentate gyrus was normal, there was severe impairment of long-term potentiation (LTP) as a result of reduced activation of NMDA receptors. After suppressing inhibition with picrotoxin, a GABA(A) receptor antagonist, NMDA receptor-mediated currents were normalized and induction of LTP was restored. Several lines of evidence suggest that inhibition in the Ts65Dn dentate gyrus was enhanced, at least in part, because of presynaptic abnormalities. These findings raise the possibility that similar changes contribute to abnormalities in learning and memory in people with DS and, perhaps, in other developmental disorders with cognitive failure.

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Figures

Figure 2.
Figure 2.
LTP is absent in the Ts65Dn DG.A, Representative evoked fEPSPs recorded from slices of 2N (left) and Ts65Dn mice (right) before (CON) and 50 min after (LTP) tetanization (thin and thick lines, respectively). Arrowheads denote stimulus artifacts that have been truncated. The vertical lines (labeled 1 and 2) indicate the interval used for the measuring the initial slope. Note the increase in the initial slope for the 2N but not the Ts65Dn DG. Each curve represents an average of five consecutive responses.B, Time course of the averaged initial slope of the fEPSP. A series of three tetanizations (arrows; Tet) applied at 5 min intervals evoked stable LTP in 2N, but failed to induce LTP in the Ts65Dn DG (open and filled circles, respectively).
Figure 5.
Figure 5.
Enhanced paired-pulse depression of the population spike in the Ts65Dn DG.A, Representative field responses recorded in the granule cell layer of slices from 2N and Ts65Dn mice (top and bottom panels, respectively). Interstimulus intervals varying from 10 to 180 msec (as denoted by the numbers under the curves) were used. The responses to the first and the second stimulus of each pair [population spike 1 (PS1) and PS2] are shown in the thick and thin lines, respectively. The population spike amplitude (PS ampl) was measured as indicated. The reduction of the population spike amplitude at short interstimulus intervals reflects PPD.B, Ratio of the amplitudes of PS2 to PS1 as a function of the interstimulus interval in 2N (open circles) and Ts65Dn (filled circles). At short intervals (<50 msec), the ratio was significantly smaller in the Ts65Dn than in the 2N DG, signifying greater PPD of the population spike in Ts65Dn.*p < 0.05;**p < 0.03. Error bars represent SEM.
Figure 7.
Figure 7.
Paired-pulse facilitation of evoked IPSCs was decreased in the Ts65Dn DG.A, Representative IPSCs evoked in granule cells in slices from 2N and Ts65Dn mice. Paired stimuli were separated by 20 msec. The amplitude of the first and second eIPSCs (A1 and A2) was measured as shown. Arrowheads (S1 and S2) denote stimulus artifacts, shown truncated.B, The averaged ratios of amplitudes for the first and second responses (i.e., eIPSC2/eIPSC1) for the 2N and Ts655Dn DG. Open bar, 2N; filled bar, Ts65Dn.*p < 0.01. The error bars inB represent SEM.
Figure 1.
Figure 1.
Basal synaptic transmission appears normal in the Ts65Dn DG.A, Representative fEPSPs recorded in the DG MML in response to different stimulation intensities. Arrowheads denote stimulus artifacts that have been truncated.B, Averaged dependence of the initial slope of fEPSPs on stimulating current. Open circle, 2N; filled circle, Ts65Dn.C, Averaged dependence of the initial slope of fEPSP on the amplitude of the presynaptic volley. Open bar, 2N; filled bar, Ts65Dn.D, Paired-pulse ratio of the second to the first fEPSP as a function of the interstimulus interval. Symbols as forB. There was no significant difference in any measure between 2N and Ts65Dn mice. Means ± SEM are shown inB-D.
Figure 3.
Figure 3.
Inadequate synaptic activation of NMDA receptors in the Ts65Dn DG is normalized by removing extracellular magnesium or depolarization.A, Representative field responses evoked by a three-stimulus (arrowheads; S1, S2, and S3), 100 Hz train in the 2N and Ts65Dn DG (thin and thick lines, respectively). 1, fEPSPs recorded in modified ACSF before application of APV. Note after the second and the third stimuli the difference in the late phases of the responses. 2, The AMPA receptor-dependent component of fEPSP recorded in an APV-containing solution. 3, The NMDA receptor-dependent component of the responses calculated as the difference in the responses recorded before and during application of APV (i.e., “1” minus “2”).B, Averaged ratios of the NMDA-AMPA responses evoked by each of the three stimuli. The ratio was significantly smaller in the Ts65Dn DG for the second and the third stimuli.*p < 0.03.C, fEPSPs evoked by three-stimuli trains in magnesium-free modified ACSF. Total fEPSPs recorded before application of APV (1), and the AMPA receptor-mediated component of fEPSPs recorded after suppression of the NMDA receptors with APV (2), were indistinguishable in the 2N and Ts65Dn DG. Consequently, the NMDA receptor-mediated component of fEPSPs, taken as “1” minus “2,” were also indistinguishable (3).D, Averaged ratios of the amplitudes of NMDA-AMPA receptor-mediated components of fEPSP in magnesium-free ACSF. There was no difference between the 2N and Ts65Dn DG.E, Whole-cell currents recorded in the DG of slices from 2N and Ts65Dn mice at holding potentials of -80 and +40 mV. The responses at -80 mV reflect activation of AMPA receptors. The responses at +40 mV reflect activation of NMDA receptors, because at this holding potential, AMPA receptors were blocked by application of NBQX.F, Ratios of the amplitudes of the whole-cell currents recorded at +40 and -80 mV. The NMDA receptor-dependent responses were similar in the 2N and Ts65Dn DG. Open bar, 2N; filled bar, Ts65Dn. The error bars inB, D, andF represent SEM.
Figure 4.
Figure 4.
Suppressing inhibition in the Ts65Dn DG restores both the NMDA receptor-mediated component of the fEPSP and LTP.A, Field responses in slices from 2N and Ts65Dn mice (thin and thick lines, respectively) recorded in ACSF containing picrotoxin. 1, Responses recorded before application of APV. 2, The AMPA receptor-mediated components of fEPSP recorded after suppression of NMDA receptors with APV. 3, The NMDA receptor-mediated component calculated as the difference between “1” and “2” (i.e., “1” minus “2”).B, Ratio of the amplitudes of NMDA-AMPA receptor-mediated components of fEPSP. There was no difference in activation of NMDA receptors in the 2N and Ts65Dn DG. Open bar, 2N; filled bar, Ts65Dn. Error bars indicate SEM.C, LTP was normal in the Ts65Dn DG after suppressing inhibition with picrotoxin. Top, Representative responses recorded from slices of 2N and Ts65Dn mice before (CON) and 50 min after (LTP) tetanization (thin and thick lines, respectively) in ACSF containing 100 μm picrotoxin. Vertical lines 1 and 2 indicate the linear parts of the responses used to measure the initial slopes. Note the increase in the initial slopes in both 2N and Ts65Dn mice. Each curve represents an average of five consecutive responses. Arrowheads denote the stimulus artifacts, shown truncated. Bottom, Time course of the averaged initial slopes. A single tetanization train (arrow; Tet) evoked stable LTP in both the 2N and Ts65Dn DG (open and filled circles, respectively).
Figure 6.
Figure 6.
The frequency of miniature IPSCs was increased in the Ts65Dn DG.A, Examples of mIPSCs recorded from granule cells in slices from 2N and Ts65Dn mice.B, Frequency histograms of mIPSC amplitudes in the DG of 2N (open circles) and Ts65Dn mice (filled circles). Inset, Ratio of mIPSC frequencies in the Ts65Dn and 2N DG as a function of mIPSC amplitude. Note that the increase of mIPSC frequency in Ts65Dn was primarily independent of mIPSC amplitude.C, Cumulative histogram of mIPSC amplitude. No difference was noted between the 2N and Ts65Dn DG. Open circles, 2N; filled circles, Ts65Dn. The error bars inB andC represent SEM.
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