Abstract
AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits and play important roles in synaptic transmission and plasticity. Here, we have investigated the development of AMPAR-mediated synaptic transmission in the hippocampus of the Fmr1 knock-out (KO) mouse, a widely used model of Fragile X syndrome (FXS). FXS is the leading monogenic cause of intellectual disability and autism spectrum disorders (ASD) and it is considered a neurodevelopmental disorder. For that reason, we investigated synaptic properties and dendritic development in animals from an early stage when synapses are starting to form up to adulthood. We found that hippocampal CA1 pyramidal neurons in the Fmr1-KO mouse exhibit a higher AMPAR-NMDAR ratio early in development but reverses to normal values after P13. This increase was accompanied by a larger presence of the GluA2-subunit in synaptic AMPARs that will lead to altered Ca2+ permeability of AMPARs that could have a profound impact upon neural circuits, learning, and diseases. Following this, we found that young KO animals lack Long-term potentiation (LTP), a well-understood model of synaptic plasticity necessary for proper development of circuits, and exhibit an increased frequency of spontaneous miniature excitatory postsynaptic currents, a measure of synaptic density. Furthermore, post hoc morphological analysis of recorded neurons revealed altered dendritic branching in the KO group. Interestingly, all these anomalies are transitory and revert to normal values in older animals. Our data suggest that loss of FMRP during early development leads to temporary upregulation of the GluA2 subunit and this impacts synaptic plasticity and altering morphological dendritic branching.
Highlights
Loss of the fragile X mental retardation protein (FMRP) in the brain causes the fragile X syndrome (FXS), a leading monogenic cause of often severe intellectual disability which is characterized by moderate-to-severe mental retardation
To investigate glutamatergic neurotransmission in hippocampal synapses of Fragile X syndrome (FXS) animals during postnatal development, we compared the amplitude of evoked postsynaptic currents (EPSCs) mediated by amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors (AMPARs) and NMDARs in acute mice hippocampal slices at different developmental stages from early development (P6) to young adult (P33)
In WT slices, an increase in the AMPAR to NMDAR ratio was observed from 0.53 ± 0.06 at P6–9 to 1.50 ± 0.21 at P > 30 (Figure 1), likely reflecting a shift from more silent synapses, i.e., synapses containing only NMDARs, to synapses with a larger content of AMPARs in the developing hippocampus (Liao et al, 1995)
Summary
Loss of the fragile X mental retardation protein (FMRP) in the brain causes the fragile X syndrome (FXS), a leading monogenic cause of often severe intellectual disability which is characterized by moderate-to-severe mental retardation. FXS is the most common inherited intellectual disability syndrome (Santoro et al, 2012) and is considered as the most common single-gene condition. FMRP is highly expressed throughout the brain, including at synapses, where it may play critical roles regulating dendritic properties, synaptogenesis, and synaptic function. FMRP is involved in mRNA regulation of multiple downstream targets including members of the glutamate receptor family, thereby impacting the normal development of neurons, synapses, and brain circuits (Contractor et al, 2015). Recent studies suggest that FMRP can directly regulate the intrinsic properties of neurons via direct interactions with potassium (Kv) and HCN channels in a cell-type-specific manner (Kalmbach et al, 2015)
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