Regulation of Synapse Development byVgatDeletion from ErbB4-Positive Interneurons

Abstract

GABA signaling has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter in in ErbB4-positive (ErbB4+) interneurons. We show that inhibitory axo-somatic synapses onto pyramidal neurons vary from one cortical layer to another; however, inhibitory synapses on axon initial segments (AISs) were similar across layers. On the other hand, PV-positive (PV+)/ErbB4+ interneurons and PV-only interneurons receive a higher number of inhibitory synapses from PV+ErbB4+ interneurons, compared with ErbB4-only interneurons. Notably, deletion from ErbB4+ interneurons reduced axo-somatic or axo-axonic synapses from PV+ErbB4+ interneurons onto excitatory neurons. This effect was associated with corresponding changes in neurotransmission. However, the mutation seemed to have little effect on inhibitory synapses onto PV+ and/or ErbB4+ interneurons. Interestingly, perineuronal nets (PNNs), extracellular matrix structures implicated in maturation, survival, protection and plasticity of PV+ interneurons, were increased in the cortex of ErbB4-Vgat-/- mice. No apparent difference was observed between males and females. These results demonstrate that of ErbB4+ interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly.GABA has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA die prematurely. To this end, we ablated in ErbB4+ interneurons in an inducible manner. We provide evidence that the formation of inhibitory as well as excitatory synapses onto excitatory neurons requires in interneurons. In particular, inhibitory axo-somatic and axo-axonic synapses are more vulnerable. Our results suggest a role of GABA in circuit assembly.

Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice

“…ErbB4 is present at postsynaptic sites of excitatory synapses onto inhibitory neurons and is implicated in their formation (3,4,8). We investigated whether these synapses are altered by adult ErbB4 deletion by using Vglut1 and PV antibodies to label, respectively, presynaptic excitatory terminals and postsynaptic dendrites of PV+ interneurons, many of which are ErbB4+ (4,13,15,16). As shown in SI Appendix, Fig.…”

“…2 H and I), indicating compromised GABA release probability. Besides perisomatic synapses, ErbB4+ neurons also form inhibitory synapses onto axon initial segments (AISs) of pyramidal neurons (3,4,16). Adult deletion seemed to have no effect on the number of these synapses (Fig.…”

“…NRG1 is produced mainly in neurons in an activity-dependent manner (11,12). On the other hand, 99% of ErbB4-positive neurons in the adult cortex and hippocampus are GABAergic (4,(13)(14)(15)(16)(17), the majority of which express parvalbumin (PV) (4,13,15,16). In adult animals, NRG1-ErbB4 signaling could promote GABAergic transmission and thus control pyramidal neuron activity (17)(18)(19)(20)(21)(22)(23)(24).…”

Vesicular GABA Transporter Is Necessary for Transplant-Induced Critical Period Plasticity in Mouse Visual Cortex

“…The donor animals also carried the Cre-dependent tdTomato reporter allele R26-Ai14 to allow the visualization of the cells in which Cre-mediated recombination occurred. It is well established that synaptic GABA release is absent in cells of the floxed Vgat mouse line that express cre recombinase (Wojcik et al, 2006;Tong et al, 2008;Saito et al, 2010;Vong et al, 2011;Wu et al, 2012;Pei et al, 2015;Hirano et al, 2016;Lin et al, 2018;Weaver et al, 2018). Loss of VGAT from presynaptic regions in MGE-derived interneurons was further assessed in vitro using immunohistochemistry of long-term cultures of Vgat ϩ/ Ϫ and Vgat Ϫ/Ϫ MGE cells.…”

Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

“…Decreased VGAT density, as well as increased bouton size or vesicle disorganization further suggest impairment of presynaptic GABAergic terminals. On its own, decreased VGAT density might explain a reduction of synapses throughout the cortical layers 76 and lead to impaired loading of GABA in the presynaptic vesicles 59 . Importantly, Sahadevan, Hembach and collaborators performed studies in Fus ∆ NLS/+ mice at earlier ages and also observed early defects of inhibitory synapses, as early as 1 month of age and progressive at 6 months of age (Sahadevan, Hembach et al, co-submitted manuscript).…”