Abnormal Presynaptic Short-Term Plasticity and Information Processing in a Mouse Model of Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity. In contrast, the presynaptic mechanisms of FXS have garnered relatively little attention and are poorly understood. Activity-dependent presynaptic processes give rise to several forms of short-term plasticity (STP), which is believed to control some of essential neural functions, including information processing, working memory, and decision making. The extent of STP defects and their contributions to the pathophysiology of FXS remain essentially unknown, however. Here we report marked presynaptic abnormalities at excitatory hippocampal synapses in Fmr1 knock-out (KO) mice leading to defects in STP and information processing. Loss of FMRP led to enhanced responses to high-frequency stimulation. Fmr1 KO mice also exhibited abnormal synaptic processing of natural stimulus trains, specifically excessive enhancement during the high-frequency spike discharges associated with hippocampal place fields. Analysis of individual STP components revealed strongly increased augmentation and reduced short-term depression attributable to loss of FMRP. These changes were associated with exaggerated calcium influx in presynaptic neurons during high-frequency stimulation, enhanced synaptic vesicle recycling, and enlarged readily-releasable and reserved vesicle pools. These data suggest that loss of FMRP causes abnormal STP and information processing, which may represent a novel mechanism contributing to cognitive impairments in FXS.

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

“…However, the overabundance of PSD scaffolding proteins, which can promote synaptic maturation, appears to be at odds with consistent findings of abnormally long, thin, and tortuous spine profiles in FXS (43). In addition, our results revealed up-regulation of many presynaptic proteins, adding weight to the idea that FMRP has phenotypically relevant presyntaptic functions (44). We observed increases in presynaptic vesicle components, including synapsin 1, VAMP2, SNAP25, syntaxin1, and the syntaxin regulators Stxbp 1 and 5, and Snph, which binds free syntaxin.…”

“…Recent studies have provided genetic evidence that genes encoding presynaptic release factors, especially SNARE complexes genes, may play important roles in susceptibility of attention-deficit/ hyperactivity disorder (45,46) and autism, two frequent endophenotypes of FXS (47,48). Together, these data raise the prospect of altered active zone structure and release dynamics at cortical synapses in FXS and may help explain abnormalities in presynaptic function seen at hippocampal synapses in the Fmr1 KO (44).…”

Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome

“…However, paired-pulse facilitation and short-term synaptic plasticity were significantly lower in Fmr1 KO mice when compared to their wild-type controls (Klemmer et al, 2011). In agreement, Deng and colleagues reported that the abnormal short-term synaptic plasticity observed in the CA1 of Fmr1 KO mice is associated with accelerated vesicle recycling, larger vesicle pools, and increased cumulative calcium influx through N-type and P/Q-type voltage gated calcium channels (Deng et al, 2011).…”

“…On the other hand, while short-term synaptic depression has been shown to be decreased in amplitude in Fmr1 KO slices (Deng et al, 2011), short-term potentiation has been found to be unaltered (Godfraind et al, 1996).…”

Reduced SNAP‐25 alters short‐term plasticity at developing glutamatergic synapses

“…Presynaptic abnormalities were reported at excitatory hippocampal synapses in a mouse model of Fragile X syndrome, leading to defects in short-term plasticity and information processing [34,35]. These changes were associated with exaggerated calcium influx in presynaptic neurons during highfrequency stimulation [34].…”