Abstract
GluA2-containing AMPA receptors (AMPARs) play a critical role in various aspects of neurodevelopment. However, the molecular mechanisms underlying these processes are largely unknown. We report here that the interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is necessary for neuron and cortical development. Using an interfering peptide (GluA2-G-Gpep) that specifically disrupts this interaction, we found that primary neuron cultures with peptide treatment displayed growth cone development deficits, impairment of axon formation, less dendritic arborization and lower spine protrusion density. Consistently, in vivo data with mouse brains from pregnant dams injected with GluA2-G-Gpep daily during embryonic day 8 to 19 revealed a reduction of cortical tract axon integrity and neuronal density in post-natal day 1 offspring. Disruption of GluA2-GAPDH interaction also impairs the GluA2-Plexin A4 interaction and reduces p53 acetylation in mice, both of which are possible mechanisms leading to the observed neurodevelopmental abnormalities. Furthermore, electrophysiological experiments indicate altered long-term potentiation (LTP) in hippocampal slices of offspring mice. Our results provide novel evidence that AMPARs, specifically the GluA2 subunit via its interaction with GAPDH, play a critical role in cortical neurodevelopment.
Highlights
AMPA-type receptors (AMPARs) are the primary mediators of fast excitatory synaptic transmission in the mammalian central nervous system, and are crucial in regulating higher brain functions such as learning and memory[1,2]
We have identified a novel interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and that an enhanced complex formation is associated with neuronal cell death[18,19,20]
Tau-1 proteins were more evenly distributed in non-treated and TAT-control peptide-treated neurons, as shown in fluorescent intensity heat maps of Tau-1 immunostaining (Fig. 2). These results indicate that disruption of GluA2-GAPDH interaction can impair growth cone development, which in turn produce deficits in axon integrity
Summary
AMPA-type receptors (AMPARs) are the primary mediators of fast excitatory synaptic transmission in the mammalian central nervous system, and are crucial in regulating higher brain functions such as learning and memory[1,2] They exist as heteromeric combinations of four subunits, namely GluA1–43. Based on in vitro and in vivo data, we demonstrated that GluA2-GAPDH disruption results in axon integrity defects, less dendritic branching, reduced spine protrusion density and fewer total neuron numbers. These histological deficits may at least be partly mediated via a reduction in GluA2-Plexin A4 interaction and p53 acetylation. Our data provides novel information on the role of GluA2-GAPDH interaction in neurodevelopment
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