Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is postulated to cause Autism Spectrum Disorders (ASD). The mammalian target of rapamycin (mTOR) is strongly implicated in ASD via upstream signaling. However, downstream regulatory mechanisms are ill-defined. We show that knockout (KO) of the eukaryotic translation Initiation Factor 4E-Binding Protein 2 (4E-BP2), an eIF4E-repressor downstream of mTOR, or eIF4E overexpression lead to increased translation of neuroligins, which are post-synaptic proteins that are causally linked to ASD. 4E-BP2-KO mice exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors: social interaction deficits, altered communication and repetitive/stereotyped behaviors. Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2 protein amounts, restore the normal excitation/inhibition ratio and rectify the social behavior deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation to inhibition balance, and its dysregulation engenders ASD-like phenotypes.
Summary The eIF4E-binding proteins (4E-BPs) repress translation initiation by preventing eIF4F complex formation. Of the three mammalian 4E-BPs, only 4E-BP2 is enriched in the mammalian brain and plays an important role in synaptic plasticity and learning and memory formation. Here we describe asparagine deamidation as brain-specific posttranslational modification of 4E-BP2. Deamidation is the spontaneous conversion of asparagines to aspartates. Two deamidation sites were mapped to an asparagine-rich sequence unique to 4E-BP2. Deamidated 4E-BP2 exhibits increased binding to the mammalian Target of Rapamycin (mTOR)-binding protein raptor, which effects its reduced association with eIF4E. 4E-BP2 deamidation occurs during postnatal development, concomitant with the attenuation of the activity of the PI3K-Akt-mTOR signalling pathway. Expression of deamidated 4E-BP2 in 4E-BP2−/− neurons yielded mEPSCs exhibiting increased charge transfer with slower rise and decay kinetics, relative to the wild type form. 4E-BP2 deamidation may represent a compensatory mechanism for the developmental reduction of PI3K-Akt-mTOR signalling.
Activity-dependent regulation of synaptic inputs in neurons is controlled by highly compartmentalized and dynamic dendritic calcium signaling. Among multiple Ca 2ϩ mechanisms operating in neuronal dendrites, voltage-sensitive Ca 2ϩ channels (VSCCs) represent a major source of Ca 2ϩ influx; however, their use-dependent implication, regulation, and function in different types of central neurons remain widely unknown. Using two-photon microscopy to probe Ca 2ϩ signaling in dendrites of hippocampal oriens/alveus interneurons, we found that intense synaptic activity or local activation of mGluR5 induced long-lasting potentiation of action potential evoked Ca 2ϩ transients. This potentiation of dendritic Ca 2ϩ signaling required mGluR5-induced intracellular Ca 2ϩ release and PKC activation and was expressed as a selective compartmentalized potentiation of L-type VSCCs. Thus, in addition to mGluR1a-dependent synaptic plasticity, hippocampal interneurons in the feedback inhibitory circuit demonstrate a novel form of mGluR5-induced dendritic plasticity. Given an implication of L-type VSCCs in the induction of Hebbian LTP at interneuron excitatory synapses, their activity-dependent regulation may represent a powerful mechanism for regulating synaptic plasticity.
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.
Mounting evidence indicates an important role of long-term synaptic plasticity in hippocampal inhibitory interneurons in learning and memory. The cellular and molecular mechanisms that underlie such persistent changes in synaptic function in interneurons remain, however, largely undetermined. A transcription-and translation-dependent form of long-term potentiation was uncovered at excitatory synapses onto hippocampal interneurons in oriens-alveus (OA-INs) which is induced by activation of type 1 metabotropic glutamate receptors (cL-LTP mGluR1 ). Here, we use (1) a combination of pharmacological siRNA knock-down and overexpression approaches to reveal the molecular mechanisms of transcriptional control via cAMP response element-binding protein (CREB) during induction, and (2) quantal analysis to identify synaptic changes during maintenance of cL-LTP mGluR1 in rat hippocampus. Induction stimulated CREB phosphorylation in OA-INs via extracellular signal-regulated protein kinase (ERK) signaling. Also, CREB knockdown impaired cL-LTP mGluR1 , whereas CREB overexpression facilitated the induction, demonstrating a necessary and permissive role of CREB via ERK signaling in transcriptional control in cL-LTP mGluR1 . Quantal analysis of synaptic responses during cL-LTP mGluR1 maintenance revealed an increased number of quanta released, corresponding to enhanced transmitter release and a larger quantal size, indicating enhanced responsiveness to individual quanta. Fluctuation analysis of synaptic currents uncovered an increase in conductance and number of functional postsynaptic receptors contributing to single quanta. Our findings indicate that CREB-dependent transcription is a necessary permissive switch for eliciting persistent presynaptic and postsynaptic quantal changes at excitatory synapses in inhibitory local circuits, uncovering cell type-specific coupling of induction and expression mechanisms during persistent synaptic plasticity which may contribute to hippocampal long-term memory processes.
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