Eps8 controls dendritic spine density and synaptic plasticity through its actin-capping activity

Abstract

Actin-based remodelling underlies spine structural changes occurring during synaptic plasticity, the process that constantly reshapes the circuitry of the adult brain in response to external stimuli, leading to learning and memory formation. A positive correlation exists between spine shape and synaptic strength and, consistently, abnormalities in spine number and morphology have been described in a number of neurological disorders. In the present study, we demonstrate that the actinregulating protein, Eps8, is recruited to the spine head during chemically induced long-term potentiation in culture and that inhibition of its actin-capping activity impairs spine enlargement and plasticity. Accordingly, mice lacking Eps8 display immature spines, which are unable to undergo potentiation, and are impaired in cognitive functions. Additionally, we found that reduction in the levels of Eps8 occurs in brains of patients affected by autism compared to controls. Our data reveal the key role of Eps8 actin-capping activity in spine morphogenesis and plasticity and indicate that reductions in actin-capping proteins may characterize forms of intellectual disabilities associated with spine defects.

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

“…Further support for this hypothesis comes from the evidence that reduced TrkB-mTOR signaling is associated with a significant decrease in protein expression of the excitatory synaptic marker PSD-95 in patients with idiopathic autism [132], suggesting fewer excitatory synapses. Lastly, knockout of the TrkB-activated actin-capping molecule Eps8 results in widespread abnormalities in spine morphology and function, decreased LTP and autism-like symptoms [115]. Taken together, these data support the model that defective TrkB-mTOR signaling disrupts spine density, morphology and function, hence playing a key role in aberrant connectivity during development and thereby in the etiology of autistic traits.…”

“…The Eps8 pathway signals through Rac, which stabilizes dendritic spines, and is opposed by Rho, which destabilizes spines [154]. We found significantly decreased Eps8 in autism vs. control fusiform gyrus [115], suggesting an imbalance in the Rac/Rho pathway influencing spine density and maturation. Together with decreased Eps8/Rac signaling, increased proBDNF in autism, acting through p75 NTR to activate Rho, may unbalance the Rac/Rho pathway.…”

“…Signaling is reduced through this pathway: reduced phosphorylation of mTOR is evident in fusiform gyrus of autism vs. control subjects [132]. No significant changes in 4E-BP1 or eIF4E protein levels were found in the same cohort [132], nor was there a difference between groups in Erk protein expression [115], demonstrating the specificity of the pathway deficit. These findings are consistent with the model that the key role BDNF plays in development of the cortex is in part mediated by activation of the PI3K-Akt-mTOR signaling pathway, which affects dendritic arborization and local protein synthesis in dendrites [96].…”

“…For example, mutations in TSC1/2 and PTEN, which activate the PI3K-Akt-mTOR pathway, lead to tuberous sclerosis complex and macrocephaly, respectively, disorders exhibiting a high prevalence of autism [40,113]. Conversely, mutations in MeCP2, a transcriptional regulator that acts through epigenetic changes in chromatin structure, reduce BDNF expression and mTOR pathway signaling and cause Rett syndrome, which like tuberous sclerosis complex and macrocephaly, is another monogenic disorder associated with high rates of autism [115,116]. This suggests that either hypo-or hyper-activation of mTOR, leading to deficient or excessive protein synthesis at synapses, may be equally disruptive; optimal synaptic function appears to occur within a narrow range [110,117].…”

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

“…It has been shown that this procedure results in significant increase in the size of PSD-95-positive puncta and in a higher extent of colocalization of PSD-95 and v-Glut1 staining, in line with a potentiation of synaptic connections. 31 To univocally ascribe the lack of potentiation to postsynaptic defects, we tested the ability of wt-GFP neurons cultured together with Het neurons (wt-GFP/Het) or Het neurons cultured together with wt-GFP neurons (Het/wt-GFP) (Figures 3j and k) to undergo synaptic potentiation. These experiments indicated that wt-GFP neurons receiving synaptic inputs from SNAP-25 Het neurons, when subjected to a chemical LTP protocol, displayed potentiation levels that were similar to their control counterparts.…”