A presynaptic role for FMRP during protein synthesis–dependent long-term plasticity in Aplysia

Abstract

Loss of the Fragile X mental retardation protein (FMRP) is associated with presumed postsynaptic deficits in mouse models of Fragile X syndrome. However, the possible presynaptic roles of FMRP in learning-related plasticity have received little attention. As a result, the mechanisms whereby FMRP influences synaptic function remain poorly understood. To investigate the cellular locus of the effects of FMRP on synaptic plasticity, we cloned the Aplysia homolog of FMRP and find it to be highly expressed in neurons. By selectively down-regulating FMRP in individual Aplysia neurons at the sensory-to-motor neuron synapse reconstituted in co-cultures, we demonstrate that FMRP functions both pre-and postsynaptically to constrain the expression of long-term synaptic depression induced by repeated pulses of FMRF-amide. In contrast, FMRP has little to no effect on long-term synaptic facilitation induced by repeated pulses of serotonin. Since other components of signaling pathways involved in plasticity appear to be conserved between Aplysia and mammalian neurons, our findings suggest that FMRP can participate in both pre-and postsynaptic regulation of enduring synaptic plasticity that underlies the storage of certain types of long-term memory.

Cytoplasmic RNA-Binding Proteins and the Control of Complex Brain Function

“…In addition, there is experimental support for a presynaptic role in synapse formation and the establishment of circuitry (Zhang et al 2001b;Hanson and Madison 2007;Bureau et al 2008;Gibson et al 2008). Recent studies on the role of the Aplysia FMRP homolog (ApFMRP) in sensory to motor neuron synaptic plasticity supports both a pre-and postsynaptic role for FMRP in regulating protein synthesis in response to synaptic stimulation (Till et al 2011). A fruitful area for further research is to connect these observations with the set of presynaptic mRNAs whose translation is regulated by FMRP ).…”

A new cis-acting motif is required for the axonal SMN-dependent Anxa2 mRNA localization

“…The local translation of transcripts represents a very important mechanism contributing to synaptic plasticity and arborization (Till et al 2011;Jung et al 2012), axonal growth (Campbell and Holt 2001;Hörnberg and Holt 2013), as well as axonal viability and neuronal development (Taylor et al 2013). In this regard, numerous studies showed that disruption of SMN function causes presynaptic abnormalities and abnormal synaptic transmission with poorly arborized axons at the neuromuscular junction (NMJ) terminals (Jablonka et al 2007;Kariya et al 2008;Kong et al 2009), suggesting that SMN might be directly involved in the regulation of axonal growth.…”

N-myristoylation regulates the axonal distribution of the Fragile X-related protein FXR2P

“…However, FMRP is also localized to axonal and presynaptic sites in both cultured neurons and the intact brain (Feng et al, 1997a; Antar et al, 2006; Price et al, 2006; Christie et al, 2009; Till et al, 2010; Akins et al, 2012). Several lines of evidence indicate that FMRP has important roles in these axonal and presynaptic domains.…”