BC1 Regulation of Metabotropic Glutamate Receptor-Mediated Neuronal Excitability

Abstract

Regulatory RNAs have been suggested to contribute to the control of gene expression in eukaryotes. Brain cytoplasmic (BC) RNAs are regulatory RNAs that control translation initiation. We now report that neuronal BC1 RNA plays an instrumental role in the proteinsynthesis-dependent implementation of neuronal excitation-repression equilibria. BC1 repression counter-regulates translational stimulation resulting from synaptic activation of group I metabotropic glutamate receptors (mGluRs). Absence of BC1 RNA precipitates plasticity dysregulation in the form of neuronal hyperexcitability, elicited by group I mGluR-stimulated translation and signaled through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. Dysregulation of group I mGluR function in the absence of BC1 RNA gives rise to abnormal brain function. Cortical EEG recordings from freely moving BC1 Ϫ/Ϫ animals show that group I mGluR-mediated oscillations in the gamma frequency range are significantly elevated. When subjected to sensory stimulation, these animals display an acute group I mGluR-dependent propensity for convulsive seizures. Inadequate RNA control in neurons is thus causally linked to heightened group I mGluR-stimulated translation, neuronal hyperexcitability, heightened gamma band oscillations, and epileptogenesis. These data highlight the significance of small RNA control in neuronal plasticity.

Dual Nature of Translational Control by Regulatory BC RNAs

“…Such alterations in the absence of BC1 RNA precipitate neuronal metabotropic glutamate receptor-mediated hyperexcitability that manifests in the form of exaggerated cortical gamma frequency oscillations, epileptogenic neuronal responses, and generalized seizures triggered by auditory stimulation (47,48). These phenotypical manifestations are consonant with the molecular role of BC RNAs as translational repressors.…”

“…Translational control mediated by BC1 RNA is important in the management of neuronal excitability (8,47,48). Lack of BC1 RNA in a BC1…”

“…Ϫ/Ϫ animal model triggers increased group I metabotropic glutamate receptor-dependent synthesis of select synaptic proteins (47). Such alterations in the absence of BC1 RNA precipitate neuronal metabotropic glutamate receptor-mediated hyperexcitability that manifests in the form of exaggerated cortical gamma frequency oscillations, epileptogenic neuronal responses, and generalized seizures triggered by auditory stimulation (47,48).…”

Abnormal mGlu 5 Receptor/Endocannabinoid Coupling in Mice Lacking FMRP and BC1 RNA

“…Recently, BC1 RNA has been proposed to regulate, under synaptic activity, two FMRP target mRNAs: FMR1 and PSD-95 (Zhong et al, 2009), further linking FMRP and BC1 in the control of neuronal mRNA translation.…”

Dual Regulation of Fragile X Mental Retardation Protein by Group I Metabotropic Glutamate Receptors Controls Translation-Dependent Epileptogenesis in the Hippocampus

“…Group I mGluR-induced epileptogenesis depends on activation of mRNA translation (Merlin et al, 1998) and is independent of transcription (Chuang et al, 2005). Recent studies indicate that the translation underlying epileptogenesis is regulated by a number of repressors including fragile X mental retardation protein (FMRP) (Chuang et al, 2005) and BC1 RNA (Zhong et al, 2009). These repressors safeguard normal subjects from group I mGluR-mediated epileptogenesis.…”