The glutamate receptor <scp>G</scp>lu<scp>N</scp>2 subunit regulates synaptic trafficking of <scp>AMPA</scp> receptors in the neonatal mouse brain

<jats:title>Abstract</jats:title><jats:p>The <jats:italic>N</jats:italic>‐methyl‐<jats:sc>d</jats:sc>‐aspartate receptor (<jats:styled-content style="fixed-case">NMDAR</jats:styled-content>) plays various physiological and pathological roles in neural development, synaptic plasticity and neuronal cell death. It is composed of two <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>1 and two <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2 subunits and, in the neonatal hippocampus, most synaptic <jats:styled-content style="fixed-case">NMDAR</jats:styled-content>s are <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">B</jats:styled-content>‐containing receptors, which are gradually replaced with <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">A</jats:styled-content>‐containing receptors during development. Here, we examined whether <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">A</jats:styled-content> could be substituted for <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">B</jats:styled-content> in neural development and functions by analysing knock‐in (<jats:styled-content style="fixed-case">KI</jats:styled-content>) mice in which <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">B</jats:styled-content> is replaced with <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">A</jats:styled-content>. The <jats:styled-content style="fixed-case">KI</jats:styled-content> mutation was neonatally lethal, although <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">A</jats:styled-content>‐containing receptors were transported to the postsynaptic membrane even without <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">B</jats:styled-content> and functional at synapses of acute hippocampal slices of postnatal day 0, indicating that <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">A</jats:styled-content>‐containing <jats:styled-content style="fixed-case">NMDAR</jats:styled-content>s could not be substituted for <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">B</jats:styled-content>‐containing <jats:styled-content style="fixed-case">NMDAR</jats:styled-content>s. Importantly, the synaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (<jats:styled-content style="fixed-case">AMPAR</jats:styled-content>) subunit <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">A</jats:styled-content>1 was increased, and the transmembrane <jats:styled-content style="fixed-case">AMPAR</jats:styled-content> regulatory protein, which is involved in <jats:styled-content style="fixed-case">AMPAR</jats:styled-content> synaptic trafficking, was increased in <jats:styled-content style="fixed-case">KI</jats:styled-content> mice. Although the regulation of <jats:styled-content style="fixed-case">AMPAR</jats:styled-content>s by <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">B</jats:styled-content> has been reported in cultured neurons, we showed here that <jats:styled-content style="fixed-case">AMPAR</jats:styled-content>‐mediated synaptic responses were increased in acute <jats:styled-content style="fixed-case">KI</jats:styled-content> slices, suggesting differential roles of <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case">A</jats:styled-content> and <jats:styled-content style="fixed-case">G</jats:styled-content>lu<jats:styled-content style="fixed-case">N</jats:styled-content>2<jats:styled-content style="fixed-case"> ...