ABSTRACT
Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary proteins that regulate crucial aspects of receptor function. Here, we investigate a mutant form of the TARP family member stargazin, described in an ID patient. Molecular dynamics analyses predicted that the ID-associated stargazin variant, V143L, weakens the overall interface of the AMPAR:stargazin complex and impairs the stability of the complex. Knock-in mice harboring the V143L stargazin mutation manifest cognitive and social deficits and hippocampal synaptic transmission defects, resembling phenotypes displayed by ID patients. In the hippocampus of stargazin V143L mice, CA1 neurons show impaired spine maturation, abnormal synaptic transmission and long-term potentiation specifically in basal dendrites, and synaptic ultrastructural alterations. These data suggest a causal role for mutated stargazin in the pathogenesis of ID and unveil a new role for stargazin in the development and function of hippocampal synapses.
Subject(s)
Calcium Channels , Intellectual Disability , Receptors, AMPA , Animals , Calcium Channels/genetics , Calcium Channels/metabolism , Hippocampus/metabolism , Humans , Intellectual Disability/genetics , Intellectual Disability/metabolism , Mice , Mutation/genetics , Receptors, AMPA/genetics , Receptors, AMPA/metabolism , Synapses/metabolism , Synaptic Transmission/geneticsABSTRACT
This study aimed to determine whether increases in flexibility following a single session predict increases in flexibility after a short-term stretching training program involving static stretching (SS) or proprioceptive neuromuscular facilitation (PNF) techniques. 70 adults (aged 18-30 years) of both sexes were randomly assigned to 2 groups: PNF (2 series of contract-relax stretching) and SS (static stretching for 1 min). Both stretching protocols were performed for 7 consecutive days. Active knee extension was evaluated before and after the first session and one day after the end of the intervention. Two-way ANOVA showed significant flexibility gains for both groups and no difference between them. The changes in flexibility after the first intervention session were strongly correlated with the changes after the training program in both groups (PNF r=0.82, p=0.001; SS: r=0.82, p=0.001). Linear regression showed that the increases in flexibility predicted the gains after both training programs (PNF: r(2)=0.67, p=0.001; SS: r(2)=0.61, p=0.005). In conclusion, the acute changes in flexibility after a single session of PNF and SS predict the gains in flexibility after longer-term training -programs.