Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits

Abstract

Background Early postnatal experience shapes NMDA receptor (NMDAR) subunit composition and kinetics at excitatory synapses onto pyramidal cells; however, little is known about NMDAR maturation onto inhibitory interneurons. Methods We combined whole-cell patch clamp recordings (n=440) of NMDAR-mediated currents from layer 4-to-2/3 synapses onto pyramidal and GFP-labeled parvalbumin-positive (PV) interneurons in visual cortex at three developmental ages (15, 30 & 45 postnatal days) with array tomography 3-D reconstructions of NMDAR subunits GluN2A- and GluN2B-positive synapses onto PV cells. Results We show that the trajectory of the NMDAR subunit switch is slower in parvalbumin-positive (PV) interneurons than in excitatory pyramidal cells in visual cortex. Notably, this differential time course is reversed in the absence of methyl-CpG-binding protein, MeCP2, the molecular basis for cognitive decline in Rett syndrome and some cases of autism. Additional genetic reduction of GluN2A subunits, which prevents regression of vision in Mecp2-knockout mice, specifically rescues the accelerated NMDAR maturation in PV cells. Conclusion We demonstrate: (1) the time course of NMDAR maturation is cell-type specific and (2) a new cell-type specific role for Mecp2 in the development of NMDAR subunit composition. Reducing GluN2A expression in Mecp2-deficient mice, which prevents the decline in visual cortical function, also prevents the premature NMDAR maturation in PV cells. Thus, circuit-based therapies targeting NMDAR subunit composition on PV cells may provide novel treatments for Rett syndrome.

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

“…Reduced excitation accompanying inhibition within adult cortical circuits in vivo is consistent with previous findings in slices demonstrating reduced excitatory glutamatergic synapse number and weaker synaptic connections or drive in pyramidal neurons (76)(77)(78)(79). Anatomical measurements have suggested increased PV + puncta, accelerated maturation of NMDA receptor subunit GluN2A, and enhanced perisomatic innervation in MeCP2 mutant mice (70,71,80), although another report found no change in PV + puncta in adult PV-MeCP2 mutant mice (81). At the same time, GABA and GAD65 levels are reduced in visual cortex (71).…”

Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype

“…This may have impacted the maturation of excitatory cortical circuits by interfering with their synaptic development resulting in an incomplete reliability of the evoked neuronal responses (72). Although brain circuit alterations in presymptomatic Mecp2-null mice have been identified (14,20,73), NMDAR subunit composition becomes disrupted in a cell-specific manner only at onset of regression (10,(24)(25)(26). By P30, pyramidal cells still exhibit immature GLUN2B-containing NMDARs, while PV cells have already completed their switch to GLUN2A and are hyperconnected onto pyramidal cells, actively silencing cortical circuits (26).…”

“…Although brain circuit alterations in presymptomatic Mecp2-null mice have been identified (14,20,73), NMDAR subunit composition becomes disrupted in a cell-specific manner only at onset of regression (10,(24)(25)(26). By P30, pyramidal cells still exhibit immature GLUN2B-containing NMDARs, while PV cells have already completed their switch to GLUN2A and are hyperconnected onto pyramidal cells, actively silencing cortical circuits (26). A low dosage of ketamine at P30 may then be the ideal intervention to specifically target such differential GluN2 expression in cortical circuits with minimal or no off-target effects.…”

“…Indeed, postmortem studies in RTT patients have shown irregular expression of NMDARs and an elevated glutamate/glutamine peak across brain regions (23,24). Similar alterations in NMDAR expression and subunit composition are also present in Mecp2-null mice (10,14,25,26). Renormalizing NMDAR composition in Mecp2-null mice by genetically deleting the NMDAR subunit, GluN2A, strikingly prevents regression of visual cortical function and preserves neuronal cortical activity (14).…”

N-Methyl-D-Aspartate Receptors, Ketamine, and Rett Syndrome: Something Special on the Road to Treatments?

“…In this issue, Mierau et al (5) and Patrizi et al (6) provide further evidence for dysregulation of NMDAR expression (5) and the therapeutic potential of ketamine (6) in mouse models of RTT. Previously, the Fagiolini laboratory reported that loss of Mecp2 is associated with hyperinnervation of pyramidal neurons by gamma-aminobutyric acidergic inhibitory interneurons in visual cortex and postweaning regression in visual acuity.…”