Abstract
Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.
Highlights
Negative feedback processes, which can enable maintenance of neuronal homeostasis, are widely observed in neuronal systems [1,2,3]
Our observation that group II metabotropic glutamate receptors activate PI3 kinase (PI3K) is of interest because group II mGluRs are implicated in epilepsy, anxiety disorders, and schizophrenia
The increase in neuronal excitability conferred by the DmGluRA112b null mutation is manifested by an increased rate of onset of a form of synaptic plasticity termed long-term facilitation (LTF) [16,17], which is induced when a motor neuron is subjected to repetitive nerve stimulation at low bath [Ca2+]
Summary
Negative feedback processes, which can enable maintenance of neuronal homeostasis, are widely observed in neuronal systems [1,2,3]. The mammalian group II metabotropic glutamate receptors, which are G-protein coupled receptors activated by glutamate, are well positioned to mediate negative feedback When localized presynaptically, these receptors can act as autoinhibitors of glutamate release [7,8,9,10]. Because these receptors are located outside of the active zone [11], activation is thought to occur only during conditions of elevated glutamate release and might serve to prevent glutamate-mediated neurotoxicity Agonists for these receptors are proposed for treatment of schizophrenia, anxiety and epilepsy, among others [12,13], but the mGluR-dependent signaling pathways that underlie these disorders remain unidentified. Many of the acute effects of group II mGluR activation on neuronal physiology have been elucidated [14,15], possible long term effects on neuronal function, such as through changes in ion channel gene expression, remain essentially unexplored
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