Chronic Neuronal Inactivity Utilizes the mTOR-TFEB Pathway to Drive Transcription-Dependent Autophagy for Homeostatic Up-Scaling.
J Neurosci
; 43(15): 2631-2652, 2023 04 12.
Article
en En
| MEDLINE
| ID: mdl-36868861
ABSTRACT
Activity-dependent changes in protein expression are critical for neuronal plasticity, a fundamental process for the processing and storage of information in the brain. Among the various forms of plasticity, homeostatic synaptic up-scaling is unique in that it is induced primarily by neuronal inactivity. However, precisely how the turnover of synaptic proteins occurs in this homeostatic process remains unclear. Here, we report that chronically inhibiting neuronal activity in primary cortical neurons prepared from embryonic day (E)18 Sprague Dawley rats (both sexes) induces autophagy, thereby regulating key synaptic proteins for up-scaling. Mechanistically, chronic neuronal inactivity causes dephosphorylation of ERK and mTOR, which induces transcription factor EB (TFEB)-mediated cytonuclear signaling and drives transcription-dependent autophagy to regulate αCaMKII and PSD95 during synaptic up-scaling. Together, these findings suggest that mTOR-dependent autophagy, which is often triggered by metabolic stressors such as starvation, is recruited and sustained during neuronal inactivity to maintain synaptic homeostasis, a process that ensures proper brain function and if impaired can cause neuropsychiatric disorders such as autism.SIGNIFICANCE STATEMENT In the mammalian brain, protein turnover is tightly controlled by neuronal activation to ensure key neuronal functions during long-lasting synaptic plasticity. However, a long-standing question is how this process occurs during synaptic up-scaling, a process that requires protein turnover but is induced by neuronal inactivation. Here, we report that mTOR-dependent signaling, which is often triggered by metabolic stressors such as starvation, is "hijacked" by chronic neuronal inactivation, which then serves as a nucleation point for transcription factor EB (TFEB) cytonuclear signaling that drives transcription-dependent autophagy for up-scaling. These results provide the first evidence of a physiological role of mTOR-dependent autophagy in enduing neuronal plasticity, thereby connecting major themes in cell biology and neuroscience via a servo loop that mediates autoregulation in the brain.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Plasticidad Neuronal
/
Neuronas
Límite:
Animals
Idioma:
En
Revista:
J Neurosci
Año:
2023
Tipo del documento:
Article
País de afiliación:
China