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. 2000 Feb 1;20(3):969-76.
doi: 10.1523/JNEUROSCI.20-03-00969.2000.

Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation

C R Raymond  1 , V L Thompson, W P Tate, W C Abraham
Affiliations

Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation

C R Raymond et al. J Neurosci. .

Abstract

We investigated the mechanisms by which previous "priming" activation of group I metabotropic glutamate receptors (mGluRs) facilitates the persistence of long-term potentiation (LTP) in area CA1 of rat hippocampal slices. Priming of LTP was elicited by either pharmacological or synaptic activation of mGluRs before a weak tetanic stimulus that normally produced only a rapidly decaying phase of LTP that did not involve protein synthesis or mGluRs. Pharmacological priming of LTP persistence by a selective group I mGluR agonist was blocked by an inhibitor of group I mGluRs and by inhibitors of translation, but not by a transcriptional inhibitor. The same mGluR agonist increased (35)S-methionine incorporation into slice proteins. LTP could also be facilitated using a synaptic stimulation priming protocol, and this effect was similarly blocked by group I mGluR and protein synthesis inhibitors. Furthermore, using a two-pathway protocol, the synaptic priming of LTP was found to be input-specific. To test for the contribution of group I mGluRs and protein synthesis to LTP in nonprimed slices, a longer duration control tetanization protocol was used to elicit a more slowly decaying form of LTP than did the weak tetanus used in the previous experiments. The persistence of the LTP induced by this stronger tetanus was dependent on mGluR activation and protein synthesis but not on transcription. Together, these results suggest that mGluRs couple to nearby protein synthesis machinery to homosynaptically regulate an intermediate phase of LTP dependent on new proteins made from pre-existing mRNA.

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Figures

Fig. 1.
Fig. 1.
Mechanisms of DHPG-induced priming of LTP in CA1 slices. A, After 1 hr of baseline recording, control slices were administered 0.5 TBS (arrow), which induced a decaying form of LTP. A 10 min priming application of DHPG (20 μm; dark bar) mildly depressed synaptic transmission but significantly enhanced the persistence of subsequent LTP. B, Delivery of either emetine (20 μm, 20 min; Emet) or cycloheximide (60 μm, 20 min; CXM, striped bar) before and during the DHPG priming period (dark bar) prevented the enhancement of LTP persistence. C, Emetine (20 μm, 20 min; striped bar) given immediately after 0.5 TBS had no effect on primed LTP (compare withB). D, Actinomycin-d (40 μm, 30 min; Act-d,striped bar), given before and during the DHPG priming period (dark bar), had no effect on the enhancement of LTP by DHPG. The slices presented in this figure were run in an interleaved manner.
Fig. 2.
Fig. 2.
Summary histogram of 35S-methionine incorporation into hippocampal slice proteins. A 30 min incubation with DHPG (20 μm) caused a significant increase in35S-methionine incorporation measured by scintillation counting. Preincubation of slices with emetine (20 μm, 30 min; Emet) reduced incorporation by 78%, confirming the efficacy of emetine in blocking protein synthesis, and blocked the DHPG-induced increase. Each of the five replications involved four pooled slices (randomly assigned) per treatment group. (*p < 0.05, significant difference from control; paired t test).
Fig. 3.
Fig. 3.
Synaptically released glutamate primes LTP by an mGluR-mediated mechanism. A, In controls, 1 TBS (light arrow) delivered 20 min after AP-5 (50 μm, 10 min; dark bar) wash induced a decaying form of LTP. Priming stimulation consisting of 2 TBS (dark arrow) in the presence of AP-5 resulted in a small, NMDA receptor-independent LTP that stabilized during AP-5 washout. LTP induced by 1 TBS subsequent to the priming stimulation was significantly enhanced. B, The group I mGluR antagonist AIDA (500 μm; dark bar), in combination with AP-5 during the priming stimulation, prevented the facilitation of LTP. C, Application of emetine (20 μm;Emet, striped bar) during the priming stimulation blocked the priming of LTP. D, To test for synapse specificity of the priming effect, two independent pathways to the same population of pyramidal cells were used. Path 1 (data not shown) received the 2 TBS priming stimulation (dark arrow) in the presence of AP-5 (dark bar). When 1 TBS was delivered to path 2 20 min later (light arrow), there was only a mild facilitation of the initial induction of LTP, which rapidly decayed to control levels. The control data from A are presented for comparison. These data demonstrate the input-specific nature of the mGluR and protein synthesis regulation of LTP. The slices A–C were run in an interleaved manner.
Fig. 4.
Fig. 4.
Role of mGluR-triggered protein synthesis in nonprimed LTP. A, The delivery of 2 TBS (arrow) in nonprimed slices (open circles) gave a moderate degree of LTP induction and persistence similar to that observed previously in DHPG-primed slices (data from Fig. 1A replotted for comparison purposes; filled circles). B, The control level of LTP for 120 min after 2 TBS is plotted (open circles; same slices as in A). Note that LTP is still decremental. Block of group I mGluRs with AIDA (500 μm, 10 min before and during the tetanus; dark bar) significantly reduced the persistence of LTP.C, Emetine (20 μm, 20 min;Emet, striped bar), applied immediately after TBS to avoid any possible effects on the initial induction mechanisms of LTP, also caused a more rapid decay of LTP over the 2 hr period. D, In contrast to emetine, actinomycin-d (40 μm;Act-d, striped bar) applied for 20 min before and after 2 TBS had no effect on LTP persistence. The slices used for this figure were run in an interleaved manner.
Fig. 5.
Fig. 5.
Summary histogram showing the effects of inhibiting transcription, translation, and group I mGluR activation on three LTP paradigms. A, The degree of LTP is represented as a percentage of their respective paradigm controls, measured at a fixed time after tetanus (1 hr time point for the 0.5 TBS groups, and 2 hr after tetanus for the 2 TBS groups). LTP induced by 0.5 TBS was unaffected by any of the drug treatments, thus reflecting the early protein synthesis-independent phase of LTP dependent on post-translational modifications. In contrast, both DHPG-primed LTP and LTP induced by 2 TBS were reduced by emetine and AIDA. Thus, both of these groups appear to engage similar mechanisms that govern the persistence of LTP, i.e., transcription-independent protein synthesis triggered by group I mGluRs. B, To control for differences in the level of induction, the persistence of LTP was taken as the rate constant of decay for the second, slower exponential function used in a double-exponential fit to the post-LTP data (Cohen and Abraham, 1996). Although statistics were performed on the rate constant data, for clarity reasons the data are plotted as the time constant of decay in minutes (i.e., the inverse of the rate constant). The drug profile of effects on decay rate for each tetanization condition was similar to that observed for LTP measured at a fixed value, as shown in A. These data confirm a role for mGluRs and protein synthesis in LTP persistence mechanisms, independent of any effects on LTP induction. (*p < 0.05, significant difference from control; Student's t test).Act-D, Actinomycin-d; Emet, emetine.
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