Preterm Birth Alters the Maturation of the GABAergic System in the Human Prefrontal Cortex

Abstract

Developmental changes in GABAergic and glutamatergic systems during frontal lobe development have been hypothesized to play a key role in neurodevelopmental disorders seen in children born very preterm or at/with low birth weight, but the associated cellular changes have not yet been identified. Here we studied the molecular development of the GABAergic system specifically in the dorsolateral prefrontal cortex, a region that has been implicated in neurodevelopmental and psychiatric disorders. The maturation state of the GABAergic system in this region was assessed in human post-mortem brain samples, from term infants ranging in age from 0 to 8 months (n = 17 male, 9 female). Gene expression was measured for 47 GABAergic genes and used to calculate a maturation index. This maturation index was significantly more dynamic in male than female infants. To evaluate the impact of premature birth on the GABAergic system development, samples from 1-month-old term (n = 9 male, 4 female) and 1-month corrected-age very preterm (n = 8 male, 6 female) infants, were compared using the same gene list and methodology. The maturation index for the GABAergic system was significantly lower (−50%, p < 0.05) in male preterm infants, with major alterations in genes linked to GABAergic function in astrocytes, suggesting astrocytic GABAergic developmental changes as a new cellular mechanism underlying preterm brain injury.

Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target

“…During adolescence, the brains of our mouse model also showed hypomyelination, a condition observed in preterm newborns ( 1 ) and suggested to be among the causes of several other neurological and behavioral disabilities ( 1 ). Our mouse model similarly reproduced a reduced number of interneurons in the cortex, which is also observed in preterm newborns ( 27 , 51 ) and frequently associated with psychiatric disorders ( 52 ). Furthermore, EEG recordings in awake head-fixed mice (similar to the resting state in humans) uncovered a decreased high-frequency power–to–low-frequency power ratio, previously associated with immature neuronal circuits ( 53 ).…”

“…Because preterm newborns nowadays may show long-term brain microstructural alterations, including decreased white matter myelination [a clinical hallmark of preterm brain disorder ( 1 )] and a reduced number of cortical interneurons ( 27 ), we investigated whether interfering with IGF-1 signaling early in development leads to similar alterations in JB1-treated mice when they are adolescents.…”

Cerebral blood flow patterns in preterm and term neonates assessed with pseudo‐continuous arterial spin labeling perfusion MRI

“…In the absence of structural damage, prematurity seems to selectively affect astrocyte maturation in the prefrontal cortex. As a consequence, PTs may exhibit a lower number of functioning synapses around TEA as compared to their FT peers, potentially explaining their greater hypoperfusion in the Fronto‐Temporal cluster (Lacaille et al, 2021 ). Supporting this interpretation, adult studies reported the presence of thinner cortices in the frontal, temporal, and parietal associative areas of individuals born PT but without overt brain injury (Schmitz‐Koep et al, 2020 ; Zubiaurre‐Elorza et al, 2012 ).…”

Lack of placental neurosteroid alters cortical development and female somatosensory function

“…The sex, completed gestational weeks and cause of death varied, but the majority were caused by sudden infant death syndrome, with no CNS infection, hemorrhage or malformation noted. Donors’ information were previously reported in ( 46 ).…”