Hypoxia-Induced Developmental Delays of Inhibitory Interneurons Are Reversed by Environmental Enrichment in the Postnatal Mouse Forebrain

Abstract

Infants born premature experience hypoxic episodes due to immaturity of their respiratory and central nervous systems. This profoundly affects brain development and results in cognitive impairments. We used a mouse model to examine the impact of hypoxic rearing (9.5-10.5% O 2 ) from postnatal day 3 to 11 (P3-P11) on GABAergic interneurons and the potential for environmental enrichment to ameliorate these developmental abnormalities. At P15 the numbers of cortical interneurons expressing immunohistochemically detectable levels of parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide were decreased in hypoxic-reared mice by 59%, 32%, and 38%, respectively, compared with normoxic controls. Hypoxia also decreased total GABA content in frontal neocortex by 31%. However, GAD67-EGFP knock-in mice reared under hypoxic conditions showed no changes in total number of GAD67-EGFP ϩ cells and no evidence of increased interneuron death, suggesting that the total number of interneurons was not decreased, but rather, that hypoxic-rearing decreased interneuron marker expression in these cells. In adulthood, PV and SST expression levels were decreased in hypoxic-reared mice. In contrast, intensity of reelin (RLN) expression was significantly increased in adult hypoxic-reared mice compared with normoxic controls. Housing mice in an enriched environment from P21 until adulthood normalized phenotypic interneuron marker expression without affecting total interneuron numbers or leading to increased neurogenesis. Our data show that (1) hypoxia decreases PV and SST and increases RLN expression in cortical interneurons during postnatal cortical development and (2) enriched environment has the capacity to normalize the interneuron abnormalities in cortex.

Learning and memory disabilities in IUGR babies: Functional and molecular analysis in a rat model

“…Synaptophysin is a presynaptic protein involved in synaptic vesicle biogenesis and trafficking that increases in parallel with the formation of synapses and is frequently used as an indicator of total synaptic vesicles pools (Valtorta et al., 2004). It is known that positive stimuli such as physical exercise and environmental enrichment increase synaptic proteins expression and normalize interneuron development, and are associated with improved synaptic plasticity and cognitive function (Abel & Rissman, 2013; Chen, Chen, Lei, & Wang, 1998; Chen et al., 2006; Hu, Ying, Gomez‐Pinilla, & Frautschy, 2009; Komitova et al., 2013). Therefore, it is possible that exercise inherent to water maze training might account for the synaptophysin normalization in IUGR rats after training such as what was observed in this study, and suggests that environmental management might reverse some of the synaptic changes associated with prenatal growth restriction postnatally.…”

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

“…Disturbances of maturation of various cellular components of the cortical neurons, such as the dendritic arbors and synapse formation, have been shown to be related to impaired cerebral growth in a preterm large-animal model (13). Recent studies have also suggested perturbed maturation of inhibitory interneurons, caudate projection neurons, and astrocytes by using animal models (14)(15)(16). Furthermore, as an underlying cause of the altered brain growth and subsequent development of cognitive dysfunction, brain injury in premature infants is thought to affect radial neuronal migration in the neocortex (17); however, this idea has not yet been rigorously investigated (6).…”

Targeting Oxidative Stress and Aberrant Critical Period Plasticity in the Developmental Trajectory to Schizophrenia

“…[36][37][38] Ultimately, interneuron dysfunction could contribute to altered sensory perception, 39 deficits in working memory, 18,40 attention, 41 and learning. 42 Recent studies have revealed anomalies in hippocampal and/or prefrontal PVI in many preclinical animal models aiming to reproduce genetic vulnerabilities [43][44][45][46] or environmental risk factors 47 such as prenatal maternal stress, 48 maternal and perinatal immune challenge, 49,50 hypoxia, 51,52 early-life iron deficiency, 53 maternal separation, 54 and social isolation. 55,56 Similarly, nongenetic developmental models also result in altered prefrontal PVI.…”