Implications of Extended Inhibitory Neuron Development

Abstract

A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.

Keywords: GABAergic inhibitory neuron; embryonic neurogenesis; functional network; gyrencephalic brain; postnatal migration.

Figure 1

The developmental processes of cortical GABAergic inhibitory neurons. Inhibitory neurons (interneurons) contribute to 20–30% of the total cortical neurons. They are generated in the ventral embryonic brain in a region called the ganglionic eminence (GE) during mid- to late-gestation (schematic shows a representative coronal section of the prenatal brain). Excitatory cortical neurons, in contrast, are generated from radial glial progenitors at the end of the first trimester and establish the cortical plate in an inside–out manner (shown in gray). Interneurons migrate from the GE and appear in the cortex early in the second trimester. Young migratory interneurons (shown in red) have a leading process and express DCX (yellow) as they migrate into the developing cortical plate (CP). The CP is the precursor to the multi-layered cortical structure. Interneuron migration into the cortex extends to the early postnatal period in gyrencephalic brains. Interneurons in the cortex increase their morphological complexity and decrease DCX expression with maturity. In adulthood, the DCX-expressing population (shown in blue) remains in cortical layer 2. Their cellular identities and functions are unknown. Within the developing cortical circuit, synapse maintenance is influenced by sensory stimuli and mediated by extracellular matrix components, such as perineuronal nets (PNNs) (green). Synapses are stabilized as PNNs increase with age. Progression from prenatal to postnatal ages is represented by the grey arrow (developmental time) directed left to right. MZ, marginal zone; CP, cortical plate.