De novo synaptogenesis induced by GABA in the developing mouse cortex

Abstract

Dendrites of cortical pyramidal neurons contain intermingled excitatory and inhibitory synapses. We studied the local mechanisms that regulate the formation and distribution of synapses. We found that local γ-aminobutyric acid (GABA) release on dendrites of mouse cortical layer 2/3 pyramidal neurons could induce gephyrin puncta and dendritic spine formation via GABA type A receptor activation and voltage-gated calcium channels during early postnatal development. Furthermore, the newly formed inhibitory and excitatory synaptic structures rapidly gained functions. Bidirectional manipulation of GABA release from somatostatin-positive interneurons increased and decreased the number of gephyrin puncta and dendritic spines, respectively. These results highlight a noncanonical function of GABA as a local synaptogenic element shaping the early establishment of neuronal circuitry in mouse cortex.

Endogenous neurosteroids influence synaptic GABAA receptors during postnatal development

“…Enhancement by neurosteroids of the GABA‐evoked depolarisation may influence the temporal window of crucial processes such as neuronal migration, morphological maturation and synapse formation . In support, allopregnanolone promotes cell proliferation both in human and rodent brain and regulates cell‐cycle and gene expression .…”

“…However, early in development (embryonic and first postnatal week), GABA A R activation results in neuronal depolarisation, as a result of a relatively high intracellular Cl − concentration, resulting from limited expression of KCC2, the principal neuronal transporter for Cl − ion extrusion . Although the validity of this developmental ionic perturbation has been challenged, under certain experimental conditions, the depolarising nature of these early GABAergic signals may be sufficient to activate voltage‐dependent calcium or sodium channels and this appears to be pivotal to the neurotrophic actions of the neurotransmitter . Furthermore, during embryogenesis, such depolarisations are primarily mediated by activation of extrasynaptic GABA A Rs, which are expressed prior to and indeed facilitate the establishment of functionally relevant synaptic connections after birth …”

GABA type a receptor trafficking and the architecture of synaptic inhibition

“…Recent proteomic strategies have vastly expanded the protein repertoire of GABAergic synapses to nearly 200 proteins by targeted purification of GABA A Rs, NL2, or gephyrin (collybistin and InSyn1 to a lesser extent) and their respective interactomes (Kang et al, ; Loh et al, ; Nakamura et al, ; Uezu et al, ). Microscopy‐based approaches encompass the fastest growing means of discovery in vitro and in vivo , including optogenetically controlled GABA A Rs (Lin et al, ), two‐photon based GABA photolysis (Oh et al, ), single‐particle‐tracking of receptor diffusion (Petrini and Barberis, ), quantitative super‐resolution imaging of gephyrin (Pennacchietti et al, ) and gephyrin recombinant antibody‐like proteins (Gross et al, ) or fluorescent super‐binding peptides (Maric et al, ). Additionally, proximity ligation assays allow for researchers to detect native protein interactions utilizing widely‐available primary antibodies (Smith et al, ; Tseng et al, ), while emerging single‐molecule fluorescence resonance energy transfer methods (smFRET) have yet to be applied.…”

Neuronal activity controls the development of interneurons in the somatosensory cortex

“…Similarly, a suppression of neurotransmitter release in single basket cells induces the formation of denser arbors and increases the number of smaller-sized boutons, without a change in the number of innervated somata (Baho and Di Cristo, 2012). In contrast, GABA signaling via the GABA-A receptor and voltage gated calcium channels induces the formation of inhibitory synapses in layer II/III pyramidal cells during early development (Oh et al, 2016). Thus, the role of GABA in circuit maturation is context dependent.…”