Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity

Abstract

Disrupted excitatory synapse maturation in GABAergic interneurons may promote neuropsychiatric disorders such as schizophrenia. However, establishing developmental programs for nascent synapses in GABAergic cells is confounded by their sparsity, heterogeneity and late acquisition of subtype-defining characteristics. We investigated synaptic development in mouse interneurons targeting cells by lineage from medial ganglionic eminence (MGE) or caudal ganglionic eminence (CGE) progenitors. MGE-derived interneuron synapses were dominated by GluA2-lacking AMPA-type glutamate receptors (AMPARs), with little contribution from NMDA-type receptors (NMDARs) throughout development. In contrast, CGE-derived cell synapses had large NMDAR components and used GluA2-containing AMPARs. In neonates, both MGE- and CGE-derived interneurons expressed primarily GluN2B subunit–containing NMDARs, which most CGE-derived interneurons retained into adulthood. However, MGE-derived interneuron NMDARs underwent a GluN2B-to-GluN2A switch that could be triggered acutely with repetitive synaptic activity. Our findings establish ganglionic eminence–dependent rules for early synaptic integration programs of distinct interneuron cohorts, including parvalbumin- and cholecystokinin-expressing basket cells.

Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function

“…Alternatively, it is possible that SYNGAP1 and the Nf1 product, neurofibromin, function in distinct subcellular compartments of GABAergic neurons and thus regulate different processes. SYNGAP1 is associated with NMDA receptor complexes at the postsynaptic membrane of glutamatergic neurons1229, raising the possibility that it also interacts with such receptors in GABAergic neurons65. In contrast, neurofibromin has been shown to localize to smooth vesiculotubular elements, cisternal stacks and multivesicular bodies in the cell body and dendrites of Purkinje cells, but not with the plasma membrane66.…”

Spatiotemporally different origins of NG2 progenitors produce cortical interneurons versus glia in the mammalian forebrain

“…The distribution of cortical interneurons correlates with the origin of their progenitors (9,10). Additional genetic studies have demonstrated that NG2 cells in the subpallium give rise to cortical interneurons (11).…”

Interneuronal GABAA receptors inside and outside of synapses

“…However blurred the picture may be, there are certain emerging trends when various properties of tonic inhibition in particular are put in the perspective of the embryonic origins of the INs. At this time, the GABAergic system of INs cannot be as clearly delineated on the basis of IN ontogeny as their glutamate receptors [74]. Nevertheless, in Fig.1 we depicted a simplified scheme for the division of hippocampal INs, based on their CGE or MGE origins, into those that may possess δ-GABA A R-mediated tonic conductances (MGE-derived) and those that do not (CGE-derived).…”

“…Surprisingly, they have been recently reported to have dual embryonic origins and distinct roles in network oscillations: the 5HT 3 -R negative OL-M INs originate from the MGE, while 5HT 3 -R positive OL-M INs are derived from the CGE [73]. This bimodal ontogeny also appears to determine the mature subunit composition of AMPARs and NMDARs of INs [74]. Perhaps analogous to how excitation is shaped by development, the specificity of GABA A R subunits may also be determined by embryonic origins.…”