Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor-dependent long-term depression - PubMed (original) (raw)

Comparative Study

Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor-dependent long-term depression

Elena D Nosyreva et al. J Neurosci. 2005.

Abstract

The presynaptic and postsynaptic properties of synapses change over the course of postnatal development. Therefore, synaptic plasticity mechanisms would be expected to adapt to these changes to facilitate alterations of synaptic strength throughout ontogeny. Here, we identified developmental changes in long-term depression (LTD) mediated by group 1 metabotropic glutamate receptors (mGluRs) and dendritic protein synthesis in hippocampal CA1 slices (mGluR-LTD). In slices prepared from adolescent rats [postnatal day 21 (P21) to P35], mGluR activation induces LTD and a long-term decrease in AMPA receptor (AMPAR) surface expression, both of which require protein synthesis. In neonatal animals (P8-P15), mGluR-LTD is independent of protein synthesis and is not associated with changes in the surface expression of AMPARs. Instead, mGluR-LTD at neonatal synapses results in large decreases in presynaptic function, measured by changes in paired-pulse facilitation and the rate of blockade by the use-dependent NMDA receptor blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate. Conversely, mGluR-LTD at mature synapses results in little or no change in presynaptic function, suggesting a postsynaptic mechanism of expression. The developmental switch in the synaptic mechanisms of LTD would differentially affect synapse dynamics and perhaps information processing over the course of postnatal development.

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Figures

Figure 4.

Figure 4.

DHPG treatment of acute hippocampal slices from adolescent rats results in a protein synthesis-dependent decrease in AMPAR surface expression. A-F, Sample Western blots of total (T) and surface (S) GluR2/3 or GluR1 subunits of the AMPA receptor. Quantitative data of the ratio of surface to total GluR2/3 or GluR1 in hippocampal slices taken either 15 or 60 min after DHPG application (100 μ

m

; 5 min). The number of experiments per group is indicated on each bar. *p < 0.05. A, B, DHPG treatment of hippocampal slices prepared from adolescent rats results in a long-term decrease of GluR2/3 and GluR1 surface expression using receptor biotinylation. C, D, Preincubation in the mGluR antagonist LY341495 (100 μ

m

) blocks DHPG-induced decreases in GluR2/3 and GluR1 surface expression. Quantitative data of the ratio of surface to total GluR2/3 or GluR1 in hippocampal slices taken 15 min after DHPG application (100 μ

m

; 5 min) in the presence of LY341495. E, F, Preincubation of slices in the protein synthesis inhibitor anisomycin (20 μ

m

) specifically blocks the late (60 min) decrease in AMPAR surface expression induced by DHPG. Error bars represent SEM.

Figure 5.

Figure 5.

DHPG does not affect the surface expression of kainate receptors in adolescent rats. A, Sample Western blot of total (T) and surface (S) GluR6/7. Quantitative data of the ratio of surface to total GluR6/7 in hippocampal slices taken either 15 or 60 min after DHPG application (100 μ

m

; 5 min). The number of experiments per group is indicated on each bar. B, Sample Western blot of total actin and actin “pulled down” (P) with avidin beads, demonstrating that intracellular proteins are not biotinylated in this assay. Error bars represent SEM.

Figure 6.

Figure 6.

NMDAR activation, but not mGluR activation, reduces AMPAR surface expression in neonatal rat slices. A, Sample Western blot of total (T) and surface (S) GluR2/3. Quantitative data of the ratio of surface to total GluR2/3 in hippocampal slices taken either 15 or 60 min after DHPG application (100 μ

m

; 5 min). The number of experiments per group is indicated on each bar. *p < 0.05. B, Sample Western blot of GluR1 and quantitative data of the same samples as those used in A. C, Sample Western blot and quantitative data of the ratio of surface to total GluR2/3 in hippocampal slices taken either 10 or 60 min after NMDA application (20 μ

m

; 3 min). D, Sample Western blot of GluR1 and quantitative data of the same samples as those used in C. Error bars represent SEM.

Figure 1.

Figure 1.

Chemically and synaptically induced mGluR-dependent LTD in neonatal hippocampus. All of the experiments shown in the figures were performed in the NMDA receptor antagonist

d

,

l

-AP-5 (100 μ

m

). A-D, Plotted are FP slopes (mean ± SEM) as a function of time from onset of DHPG or conditioning stimulation. A, DHPG (100 μ

m

; 5 min; arrow) induces LTD of FP slope values, which is similar in magnitude in neonatal (P8-P15) and adolescent (P21-P35) rats. B, LTD induced with PP-LFS is enhanced in slices from neonatal rats compared with adolescent rats. C, DHPG-LTD in neonatal rats is blocked by the broad mGluR antagonist LY341495 (100 μ

m

). D, PP-LFS-induced LTD in neonatal rats is inhibited by LY341495 (100 μ

m

). Representative FPs (average, 1 min) are shown for each experiment at the times indicated by the numbers on the graph. Calibration: 0.5 mV, 5 ms.

Figure 2.

Figure 2.

The protein synthesis dependence of chemically induced mGluR-LTD is developmentally regulated. A, C, DHPG-induced LTD in slices from neonatal rats is insensitive to the protein synthesis inhibitors anisomycin (20 μ

m

; A) or cycloheximide (60 μ

m

; C). B, D, In contrast, anisomycin (B) and cycloheximide (D) block DHPG-LTD in adolescent rats.

Figure 3.

Figure 3.

The protein synthesis dependence of synaptically induced mGluR-LTD is developmentally regulated. A, C, LTD induced with synaptic stimulation (PP-LFS) in neonatal rats is not affected by anisomycin (A) or cycloheximide (C). B, PP-LFS-induced LTD in slices from adolescent rats is blocked by anisomycin. D, The ability of anisomycin to block PP-LFS-induced LTD is significantly correlated with the postnatal age of the rats.

Figure 7.

Figure 7.

mGluR-LTD in neonatal rats is associated with changes in presynaptic function. A, Representative FPs elicited by paired-pulse stimulation in P8-P15 and P21-P35 hippocampal slices during baseline (1) and after 50 min of DHPG onset (2). Calibration: 0.5 mV, 20 ms. DHPG trace (2) was scaled to baseline FP1 amplitude for comparison of PPF changes within a single experiment. Note that, in the P8 rat, the second response is facilitated but is unchanged at P29. B, Group data of PPF (FP2 slope/FP1 slope as a percentage of pre-DHPG baseline) change during LTD in neonatal and adolescent animals. The asterisk indicates that PPF changes are greater in neonatal than adolescent rats (p < 0.02). C, DHPG-induced LTD of FP1 was not different among age groups. D, Representative NMDAR FPs taken at the times indicated in E and F from a P13 or P33 rat. Calibration: 0.2 or 0.1 mV (as indicated), 10 ms. E, F, Group average of decay of NMDAR FP amplitude in the presence of MK801 (10 μ

m

) in control or after DHPG (100 μ

m

; 5 min) treatment of neonatal (E) or adolescent (F) rat slices. Fast component (τ1) is slower in DHPG-treated neonatal slices.

Figure 8.

Figure 8.

CB1R activation is not required for mGluR-LTD in neonatal slices. A, CB1R antagonist AM281 (1 μ

m

) is effective in the hippocampal slice preparation and inhibits synaptic depression induced by a brief application of the CB1R agonist WIN55,212-2 (WIN 55; 2 μ

m

; 10 min). Solid bars indicate the time of drug application. Representative FPs are taken at the times indicated by the numbers on the graph. Calibration: 0.5 mV, 5 ms. B, C, Preincubation in AM281 does not affect LTD induced with DHPG (B) or PP-LFS (C) in neonatal rat slices.

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