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.

Common basis for orofacial clefting and cortical interneuronopathy

“…Some degree of overlap between the programs regulating development of the lip, palate, and cINs is suggested by several mutual genetic regulators including Wnt5a 59 – 61 , Gad1 62 , 63 , Vax1 64 – 66 , and Gabrb3 63 , 67 , 68 . These cell populations also share inherent sensitivity to environmental insults, including prenatal alcohol exposure 26 . The concurrent impact of alcohol on the developing brain and face has been extensively documented and presents significant overlap with our emerging understanding of the OFC face-brain relationship 69 .…”

“…Addressing this fundamental gap, we show here in the mouse that nonsyndromic OFCs can co-occur with significant disruptions in GABAergic cortical interneuron (cIN) development. Though they comprise only 10–25% of neurons in the neocortex, the dynamic modulation of cortical activity exerted by cINs shapes cortical maturation, underlies multiple aspects of learning and memory, and is requisite for normal cognition 26 , 27 . Disruption of cIN development has been extensively implicated in neurodevelopmental and neuropsychiatric illnesses that have symptomatic overlap with traits observed in populations with OFCs 26 , 28 – 36 .…”

“…Though they comprise only 10–25% of neurons in the neocortex, the dynamic modulation of cortical activity exerted by cINs shapes cortical maturation, underlies multiple aspects of learning and memory, and is requisite for normal cognition 26 , 27 . Disruption of cIN development has been extensively implicated in neurodevelopmental and neuropsychiatric illnesses that have symptomatic overlap with traits observed in populations with OFCs 26 , 28 – 36 . Our findings are the first to link OFCs with abnormal cIN development and represent an important foundational step in understanding neurobehavioral deficits that contribute significantly to the morbidity of common birth defects.…”

Deletion of Semaphorin 3F in Interneurons Is Associated with Decreased GABAergic Neurons, Autism-like Behavior, and Increased Oxidative Stress Cascades

“…Additive factors such as terbutaline and maternal stress during gestation produce autistic-like behaviors, spontaneous recurrent convulsive seizures, epileptiform EEGs, and hippocampal gliosis in rodents similar to patients with autism and epilepsy [7]. Those gene–environment interactions may target cortical interneurons, predisposing to autism and epilepsy [8]. Functional genomic work has implicated a wide array of transcriptome pathways (synaptic, immune, cell cycle, DNA damage, WNT signaling, cortical patterning/differentiation in ASD) [9].…”

Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken

“…Accordingly, it is important to establish an experimental model. Environmental and genetic factors, and their interactions, play important roles in the phenotypic generation and pathogenesis [ 10 , 11 , 12 ]. Nutritional factors can induce fatty liver in chickens [ 13 ].…”