Persistent Transcription- and Translation-Dependent Long-Term Potentiation Induced by mGluR1 in Hippocampal Interneurons

Abstract

Hippocampal interneurons synchronize the activity of large neuronal ensembles during memory consolidation. Although the latter process is manifested as increases in synaptic efficacy which require new protein synthesis in pyramidal neurons, it is unknown whether such enduring plasticity occurs in interneurons. Here, we uncover a long-term potentiation (LTP) of transmission at individual interneuron excitatory synapses which persists for at least 24 h, after repetitive activation of type-1 metabotropic glutamate receptors [mGluR1-mediated chemical late LTP (cL-LTP mGluR1 )]. cL-LTP mGluR1 involves presynaptic and postsynaptic expression mechanisms and requires both transcription and translation via phosphoinositide 3-kinase/mammalian target of rapamycin and MAP kinase kinaseextracellular signal-regulated protein kinase signaling pathways. Moreover, cL-LTP mGluR1 involves translational control at the level of initiation as it is prevented by hippuristanol, an inhibitor of eIF4A, and facilitated in mice lacking the cap-dependent translational repressor, 4E-BP. Our results reveal novel mechanisms of long-term synaptic plasticity that are transcription and translation-dependent in inhibitory interneurons, indicating that persistent synaptic modifications in interneuron circuits may contribute to hippocampaldependent cognitive processes.

A recollection of mTOR signaling in learning and memory

“…However, this LTP still requires protein synthesis, suggesting that not all proteins required for L-LTP are regulated by 4EBP2. LTP of inhibitory neurons induced by mGluR stimulation was also enhanced in the absence of 4EBP2 (Ran et al 2009). mGluR-LTD in excitatory neurons lacking 4EBP2 is similarly enhanced, and activation of 4EBP2 explains the sensitivity of mGluR-LTD to rapamycin in wild-type neurons observed in this study (Banko et al 2006).…”

CREB-Dependent Transcriptional Control and Quantal Changes in Persistent Long-Term Potentiation in Hippocampal Interneurons

“…At 48 h posttransfection, slices received a chemical induction protocol (sham, single, or repeated mGluR1 stimulation) as previously described (Ran et al, 2009). The chemical induction protocol consisted of three applications (10 min duration each at 30 min intervals) of the mGluR1/5 agonist ( S)-3,5-dihydroxyphenylglycine (DHPG; 5 M, Tocris Bioscience) in the presence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 25 M, Ascent Scientific).…”

“…Recently, a late-phase LTP (L-LTP), lasting 24 h, was uncovered at synapses onto oriens-alveus interneurons (OAINs) that are induced by repeated activation of type 1 metabotropic glutamate receptors (chemical mGluR1-mediated late LTP; cL-LTP mGluR1 ) (Ran et al, 2009), which requires ERK signaling and is transcription and translation dependent (Ran et al, 2009). By analogy to pyramidal cell L-LTP (Abel et al, 1997), cL-LTP mGluR1 is an interesting candidate mechanism for learning-related, long-term synaptic plasticity in interneurons.…”

“…mTOR signaling via ERK regulates cap-dependent translation during cL-LTP mGluR1 induction (Ran et al, 2009), indicating that translational control mechanisms during synaptic plasticity in interneurons are similar to those in pyramidal cells (Banko et al, 2005) and conserved across cell types. Mechanisms regulating transcription during cL-LTP mGluR1 remain undetermined.…”

“…Changes in evoked and miniature synaptic currents during cL-LTP mGluR1 in interneurons implicate presynaptic and postsynaptic maintenance mechanisms (Ran et al, 2009). In pyramidal neurons, quantal analysis indicated a presynaptic increase in the number of quanta released with unchanged postsynaptic response to individual quanta during L-LTP (Bolshakov et al, 1997), suggesting that synaptic locus of persistent plasticity may differ across cell types.…”