Gene-environment interactions in cortical interneuron development and dysfunction: A review of preclinical studies

Abstract

Cortical interneurons (cINs) are a diverse group of locally projecting neurons essential to the organization and regulation of neural networks. Though they comprise only ∼20% of neurons in the neocortex, their dynamic modulation of cortical activity is requisite for normal cognition and underlies multiple aspects of learning and memory. While displaying significant morphological, molecular, and electrophysiological variability, cINs collectively function to maintain the excitatory-inhibitory balance in the cortex by dampening hyperexcitability and synchronizing activity of projection neurons, primarily through use of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Disruption of the excitatory-inhibitory balance is a common pathophysiological feature of multiple seizure and neuropsychiatric disorders, including epilepsy, schizophrenia, and autism. While most studies have focused on genetic disruption of cIN development in these conditions, emerging evidence indicates that cIN development is exquisitely sensitive to teratogenic disruption. Here, we review key aspects of cIN development, including specification, migration, and integration into neural circuits. Additionally, we examine the mechanisms by which prenatal exposure to common chemical and environmental agents disrupt these events in preclinical models. Understanding how genetic and environmental factors interact to disrupt cIN development and function has tremendous potential to advance prevention and treatment of prevalent seizure and neuropsychiatric illnesses.

Keywords: Cortical development; Developmental neurotoxicity; Gene-environment; Interneuron; Schizophrenia; Seizure.

Figure 1. Cortical Interneuron Development

Upper left: Three-dimensional reconstruction of the brain and face of a fetal mouse derived from high resolution magnetic resonance microscopy sections. The light green square indicates plane of section for the schematic illustration to the right. Right: Schematic illustration of the developing telencephalon at approximately embryonic day 15. Dark green arrows indicate possible routes of cortical interneuron (cIN) tangential migration from the subpallial proliferative zones to the cortex. cINs born during the early neurogenic period primarily enter the cortex via a superficial stream within the marginal zone (1,3), while those that are born during the late neurogenic period enter via a deeper stream into the intermediate and subventricular zones (2). Subsequent to tangential migration, cINs align along either side of the cortical plate before undergoing radial migration and integration. LGE, MGE, CGE: lateral, medial, and caudal ganglionic eminences. POA: preoptic area.

Figure 2. Cortical Interneuron Development is Highly Sensitive to Teratogenic Disruption

Left: Timeline of critical periods in human and mouse cortical interneuron (cIN) ontogenesis. Right: Common teratogens target key events in cIN development including initial fate specification, proliferation, tangential migration from the subpallium to the cortex, circuit integration, and adoption of mature expression and connective profiles. Highlighting the emergent nature of the field, 68% (n=15/22) of the studies supporting this list were published within the past 5 years. Asterisks (*) denote areas where further experimental evidence is required to substantiate the association. dpc: days post conception, E: embryonic day, PD: postnatal day.