Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus

Abstract

Activity-dependent bidirectional modifications of excitatory synaptic strength are essential for learning and storage on new memories. Research on bidirectional synaptic plasticity has largely focused on long-term potentiation (LTP) and long-term depression (LTD) mechanisms that rely on the activation of NMDA receptors. In principle, metabotropic glutamate receptors (mGluRs) are also suitable to convert synaptic activity into intracellular signals for synaptic modification. Indeed, dysfunction of a form of LTD that depends on Type I mGluRs (mGluR-LTD), but not NMDARs, has been implicated in learning deficits in aging and mouse models of several neurological conditions, including Fragile X syndrome and Alzheimer's disease. To determine whether mGluR activation can also induce LTP in the absence of NMDAR activation, we examined in hippocampal slices from rats and mice, an NMDAR-independent form of LTP previously characterized as dependent on voltage-gated Ca 2ϩ channels. We found that this form of LTP requires activation of Type I mGluRs and, like mGluR-LTD but unlike NMDAR-dependent plasticity, depends crucially on protein synthesis controlled by fragile X mental retardation protein and on Arc signaling. Based on these observations, we propose the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs.

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

“…Arc's well-studied ability to alter synaptic efficacy by endocytosis of AMPA receptors established it as a critical regulator of synaptic plasticity 14,17,188,195 . Whereas this mechanism of activity-dependent removal of glutamate receptors supports Arc's role in mediating long-term depression (LTD) [196][197][198][199] , it does not explain the absence of stable long-term potentiation (LTP) observed in Arc knock-out mice 4 . Because late-LTP is considered a critical cellular mechanism underlying memory consolidation, the molecular and cellular mechanism by which Arc supports memory stabilization has remained elusive.…”

Administration of Bacterial Lipopolysaccharide during Early Postnatal Ontogenesis Induces Transient Impairment of Long-Term Synaptic Plasticity Associated with Behavioral Abnormalities in Young Rats

“…Today, it is evident that LTP can involve several mechanisms depending on the cell type, development stage, and conditions in which the synapses operate [14,18,30]. The postsynaptic Ca 2+ influx is essential for the induction of LTP [31], and different forms of LTP are induced by spatially discrete Ca 2+ sources [18,32,33]. One of the critical Ca 2+ -permeable receptors involved in hippocampal synaptic plasticity is the N-methyl-D-aspartate (NMDA) type of glutamate receptor [18,34].…”

“…The coexistence of distinct activity-dependent systems of synaptic plasticity based on discrete Ca 2+ sources, such as NMDARs and metabotropic glutamate receptors (mGluRs), has been recently described in the same synapses [33]. Their relative roles in plasticity may change in some pathological conditions.…”

Epidural Electrotherapy for Epilepsy

“…The sHFS stimulation did not block the interictal‐like activity (Figure e); rather, it showed an increase of the event frequency. It is probably due to increased activity of normal signal transmission by repetitive sHFS, which has been known to be a type of HFS‐induced synaptic plasticity . These results indicate the selectivity of sHFS on the suppression of epileptiform activities.…”