Abstract

Throughout early phases of brain development, the two main neural signaling mechanisms—excitation and inhibition—are dynamically sculpted in the neocortex to establish primary functions. Despite its relatively late formation and persistent developmental changes, the GABAergic system promotes the ordered shaping of neuronal circuits at the structural and functional levels. Within this frame, interneurons participate first in spontaneous and later in sensory-evoked activity patterns that precede cortical functions of the mature brain. Upon their subcortical generation, interneurons in the embryonic brain must first orderly migrate to and settle in respective target layers before they can actively engage in cortical network activity. During this process, changes at the molecular and synaptic level of interneurons allow not only their coordinated formation but also the pruning of connections as well as excitatory and inhibitory synapses. At the postsynaptic site, the shift of GABAergic signaling from an excitatory towards an inhibitory response is required to enable synchronization within cortical networks. Concomitantly, the progressive specification of different interneuron subtypes endows the neocortex with distinct local cortical circuits and region-specific modulation of neuronal firing. Finally, the apoptotic process further refines neuronal populations by constantly maintaining a controlled ratio of inhibitory and excitatory neurons. Interestingly, many of these fundamental and complex processes are influenced—if not directly controlled—by electrical activity. Interneurons on the subcellular, cellular, and network level are affected by high frequency patterns, such as spindle burst and gamma oscillations in rodents and delta brushes in humans. Conversely, the maturation of interneuron structure and function on each of these scales feeds back and contributes to the generation of cortical activity patterns that are essential for the proper peri- and postnatal development. Overall, a more precise description of the conducting role of interneurons in terms of how they contribute to specific activity patterns—as well as how specific activity patterns impinge on their maturation as orchestra members—will lead to a better understanding of the physiological and pathophysiological development and function of the nervous system.

Highlights

  • During early development, mammalian brains can be functionally characterized by the progressive emergence of distinct cortical activity patterns which are essential for the establishment of basic functions of the cerebral cortex (Blankenship and Feller, 2010; Kilb et al, 2011; Kirkby et al, 2013)

  • Immature cortical networks have a unique capacity to stabilize their network activity, even if strong changes in GABA signaling are introduced e.g., by alterations in the absolute number of GABAergic interneurons in neocortical cultures (Sukenik et al, 2021; Xing et al, 2021), genetic changes of total GABA content in the brain (Tamamaki et al, 2003), or modulations of chloride homeostasis (Pfeffer et al, 2009; Graf et al, 2021). This stability underlines the great source of plasticity of the neuronal system in general, but is especially remarkable given the suggested key function of GABAergic interneurons for the balancing of excitation and inhibition, and coordinating network activity during development (Bonifazi et al, 2009; Le Magueresse and Monyer, 2013; Modol et al, 2020; Baruchin et al, 2021)

  • GABAergic interneurons keep this crucial role in mature networks with some critical modifications (Markram et al, 2004; Bartos et al, 2007; Tremblay et al, 2016)

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Summary

Introduction

Mammalian brains can be functionally characterized by the progressive emergence of distinct cortical activity patterns which are essential for the establishment of basic functions of the cerebral cortex (Blankenship and Feller, 2010; Kilb et al, 2011; Kirkby et al, 2013). GABA release from SST interneurons leads to the expression of the scaffolding protein gephyrin and dendritic spine formation by recruitment and activation of GABAA receptors in layer 2/3 cortical pyramidal neurons in neonatal mice (Oh et al, 2016).

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