AMPA receptor deletion in developing MGE-derived hippocampal interneurons causes a redistribution of excitatory synapses and attenuates postnatal network oscillatory activity

Gülcan Akgül,Chris J Mcbain

doi:10.1038/s41598-020-58068-6

Abstract

Inhibitory interneurons derived from the medial ganglionic eminence represent the largest cohort of GABAergic neurons in the hippocampus. In the CA1 hippocampus excitatory synapses onto these cells comprise GluA2-lacking, calcium-permeable AMPARs. Although synaptic transmission is not established until early in their postnatal life, AMPARs are expressed early in development, however their role is enigmatic. Using the Nkx2.1-cre mouse line we genetically deleted GluA1, GluA2, GluA3 selectively from MGE derived interneurons early in development. We observed that the number of MGE-derived interneurons was preserved in mature hippocampus despite early elimination of AMPARs, which resulted in >90% decrease in spontaneous excitatory synaptic activity. Of particular interest, excitatory synaptic sites were shifted from dendritic to somatic locations while maintaining a normal NMDAR content. The developmental switch of NMDARs from GluN2B-containing early in development to GluN2A-containing on maturation was similarly unperturbed despite the loss of AMPARs. Early network giant depolarizing potential oscillatory activity was compromised in early postnatal days as was both feedforward and feedback inhibition onto pyramidal neurons underscoring the importance of glutamatergic drive onto MGE-derived interneurons for hippocampal circuit function.

Highlights

Inhibitory interneurons derived from the medial ganglionic eminence represent the largest cohort of GABAergic neurons in the hippocampus
Loss of AMPARs caused near elimination of AMPAR-mediated spontaneous excitatory postsynaptic currents commencing in the early postnatal period, which was accompanied by a change in the release probability of evoked transmission
We first determined whether the loss of function of GluA1, 2 and 3 AMPAR subunits impacted the number of MGE-derived, Nkx2.1lineage interneurons observed in mature hippocampus

Summary

Introduction

Inhibitory interneurons derived from the medial ganglionic eminence represent the largest cohort of GABAergic neurons in the hippocampus. We observed that the number of MGE-derived interneurons was preserved in mature hippocampus despite early elimination of AMPARs, which resulted in >90% decrease in spontaneous excitatory synaptic activity. The developmental switch of NMDARs from GluN2B-containing early in development to GluN2A-containing on maturation was unperturbed despite the loss of AMPARs. Early network giant depolarizing potential oscillatory activity was compromised in early postnatal days as was both feedforward and feedback inhibition onto pyramidal neurons underscoring the importance of glutamatergic drive onto MGE-derived interneurons for hippocampal circuit function. Nkx2.1-positive MGE progenitors give rise to the vast majority of parvalbumin- (PV), somatostatin(SOM) and nNOS-containing Ivy and neurogliaform interneurons1,2 These interneuron subpopulations often occupy distinct anatomical subregions within the hippocampus and target different domains of their downstream targets all MGE-derived interneurons in the CA1 hippocampus typically express synaptic GluA2-lacking, Ca2+-permeable AMPARs (CP-AMPARs). Cell numbers were largely unchanged we observed a major redistribution of excitatory synapses away from dendritic sites onto the somatic compartment

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Results

Conclusion