Yoon, Y. J. | Search bioRxiv

bioRxiv2021

Activity-dependent LTP in the dentate gyrus promotes epileptic seizures

Epilepsy is a devastating brain disorder whose cellular mechanisms remain poorly understood. Excitatory mossy cells (MCs) in the dentate gyrus of the hippocampus are implicated in temporal lobe epilepsy, the most common form of focal epilepsy in adults. However, the role of MCs during initial seizures, before MC loss occurs, is unclear. Here, we show that initial seizures induced with kainic acid (KA) intraperitoneal injection in adult mice, a well-established model of experimental epilepsy, not only increased MC and granule cell (GC) activity in vivo, but also triggered a BDNF-dependent long-term potentiation at MC-GC synapses (MC-GC LTP). In vivo induction of MC-GC LTP worsened KA-induced seizures, whereas selective MC silencing and Bdnf genetic removal from GCs, which abolishes LTP, were both anti-epileptic. Thus, initial seizures strengthen MC-GC synaptic transmission, thereby promoting epileptic activity. Our findings reveal a potential mechanism of epileptogenesis that may help develop therapeutic strategies for early intervention.

neuroscience↗

bioRxiv2021

Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals

Learning and memory critically rely on long-lasting, synapse-specific modifications. While postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remains unclear. Here, we examined the hippocampal mossy fiber (MF)-CA3 synapse which expresses both structural and functional presynaptic plasticity. We report that MF boutons synthesize protein locally and contain ribosomes. Long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with translation-dependent enlargement of MF boutons. Moreover, increasing in vitro and in vivo MF activity enhanced protein synthesis in MFs. Remarkably, deletion of presynaptic Fragile X mental retardation protein (FMRP), an RNA-binding protein expressed in MF boutons and previously implicated in local postsynaptic protein synthesis-dependent plasticity, blocked structural and functional MF-LTP, suggesting that FMRP is a critical regulator of presynaptic function. Thus, presynaptic FMRP and protein synthesis dynamically control presynaptic structure and function in the mature brain. HighlightsO_LIMossy fiber boutons (MFBs) synthesize protein locally and contain ribosomes C_LIO_LILocal presynaptic translation is increased by in vitro and in vivo GC activity C_LIO_LIMFB structural plasticity relies on de novo protein synthesis. C_LIO_LIPresynaptic FMRP is required for MF-CA3 structural and functional plasticity C_LI In BriefMonday et al. report that FMRP and protein synthesis in hippocampal mossy fiber boutons mediate functional and structural presynaptic plasticity.

neuroscience↗