Periadolescent Maturation of GABAergic Hyperpolarization at the Axon Initial Segment

Abstract

Neuronal chloride levels are developmentally regulated. Early in life, high intracellular concentrations support chloride efflux and depolarization at GABAergic synapses. In mouse, intracellular chloride decreases over the first postnatal week in the somatodendritic compartment, eventually supporting mature, hyperpolarizing GABAergic inhibition. In contrast to this dendritic switch, it is less clear how GABAergic signaling at the axon initial segment (AIS) functions in mature pyramidal cells, as reports of both depolarization and hyperpolarization have been reported in the AIS past the first postnatal week. Here, we show that GABAergic signaling at the AIS of prefrontal pyramidal cells, indeed, switches polarity from depolarizing to hyperpolarizing but does so over a protracted periadolescent period. This is the most delayed maturation in chloride reversal in any structure studied to date and suggests that chandelier cells, which mediate axo-axonic inhibition, play a unique role in the periadolescent maturation of prefrontal circuits.

Unique Maturation Trajectories of Basket and Chandelier Cells in the Neocortex

“…The results presented by Miyamae et al (2017) on the absence of age-related changes in short-term depression complement previous findings on the maturation of synaptic physiology in neocortical pyramidal cells (Zhang, 2004). The shortterm dynamics of synaptic connections between neocortical pyramidal cells has been shown to be age-dependentsynapses are strongly depressing at puberty (P12) but they gradually transition to being facilitating during adulthood (ϳP50) (Etherington and Williams, 2011; Ramaswamy and Markram, 2015).…”

“…BCs selectively innervate the perisomatic region of target cells to bring about fast and powerful inhibition and, thus, influence cortical function and dysfunction (Kawaguchi and Kubota, 1997;. For example, BCs provide feedforward inhibition in the neocortex, maintain highfrequency cortical oscillations (Pouille and Scanziani, 2001;Bartos et al, 2007;Cardin et al, 2009), and are implicated in cognitive diseases, such as schizophrenia (Lewis et al, 2005;Gonzalez-Burgos and Lewis, 2008). ChCs have an exquisite axonal morphology that enables them to synapse specifically on to the axon initial segment of target cells and strategically control spiking activity (Somogyi et al, 1982).…”

“…Interestingly, Miyamae et al 2017found that the short-term dynamics of excitatory synapses onto L1/L2 BCs and ChCs remained robustly depressing from puberty to adulthood. For a train of incoming stimuli, depressing synapses show the strongest response to the first input, followed by an exponential decrease in response strength and reliability for subsequent inputs (Abbott et al, 1997). Therefore, preserving short-term depression of synaptic input on to L1/L2 BCs and ChCs throughout development could provide these cells with the excitatory drive required to elicit the strongest response to the first input, and reliably inhibit neighboring neurons.…”

“…It is thought that fast-spiking activity in BCs and ChCs enables frequency tuning and synchrony of network oscillations in the gamma band (30 -100 Hz) (Bartos et al, 2007). Gamma oscillations have been proposed to regulate higher brain functions, such as visual attention, memory formation, and sensory processing (Buzsáki and Wang, 2012).…”

Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex

“…Inhibitory neurotransmission onto pyramidal neurons in the PFC is remodeled during the adolescent period (Le Magueresse and Monyer 2013; Lewis and Melchitsky 2013;Rinetti-Vargas et al 2017). Recent work in rodents is illuminating the cell type specificity of these changes and the potential role of pubertal processes in their regulation.…”