Reduced Hippocampal Dendrite Branching, Spine Density and Neurocognitive Function in Premature Rabbits, and Reversal with Estrogen or TrkB Agonist Treatment

Abstract

Preterm-born children suffer from neurological and behavioral disorders. Herein, we hypothesized that premature birth and non-maternal care of preterm newborns might disrupt neurobehavioral function, hippocampal dendritic arborization, and dendritic spine density. Additionally, we assessed whether 17β-estradiol (E2) replacement or the TrkB receptor agonist, 7,8-dihydroxyflavone (DHF), would reverse compromised dendritic development and cognitive function in preterm newborns. These hypotheses were tested by comparing preterm (E28.5) rabbit kits cared and gavage-fed by laboratory personnel and term-kits reared and breast-fed by their mother doe at an equivalent postconceptional age. Neurobehavioral tests showed that both premature-birth and formula-feeding with non-maternal care led to increased anxiety behavior, poor social interaction, and lack of novelty preference compared with term-kits. Dendritic branching and number of total or mushroom dendritic spines were reduced in the CA1 field of preterm-kits compared with term controls. While CDC42 and Rac1/2/3 expression levels were lower, RhoA-activity was higher in preterm-kits compared with term controls. Both E2 and DHF treatment reversed prematurity-induced reduction in spine density, reduced total RhoA-GTPase levels, and enhanced cognitive function. Hence, prematurity and non-maternal care result in cognitive deficits, and reduced dendritic arbors and spines in CA1. E2 replacement or DHF treatment might reverse changes in dendritic spines and improve neurodevelopment in premature infants.

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

“…Intrauterine growth restriction is an important contributor to poor perinatal outcomes, particularity in preterm born infants [see (163)]. Reduced dendritic branching and spine immaturity have also been reported in the CA1 region of hippocampus in a model of preterm birth in rabbit kits (30) and in the granular layer of the dentate gyrus in a maternal inflammatory activation (using i.p. poly I:C exposure) model in mice (164).…”

“…Other, non-inflammatory, post-natal contributors to EoP may include hyperoxia ( 25 ), as the ex utero environment is relatively high in oxygen compared to the in utero environment ( 26 ), and reduced exposure to maternal hormones, such as estrogen and other neuroactive precursors ( 27 ). While there has been little follow up on the estrogen hypothesis clinically ( 28 ), recent animal models have suggested a potential protective effect ( 4 , 29 , 30 ). That hyperoxia plays a role in EoP is also supported by animal studies ( 31 – 33 ).…”

Rac-maninoff and Rho-vel: The symphony of Rho-GTPase signaling at excitatory synapses

“…Conversely, KD or inhibition of the RhoA-GEF GEF-H1/Lfc increases spine density in hippocampal neurons [ 164 ]. Besides these postnatal RhoA signalling events, recent studies have looked at prenatal development and observed a similar inhibitory role for RhoA at these earliest stages of synaptogenesis in both rabbits [ 165 ] and organoids derived from human induced pluripotent stem cells [ 166 ]. However, it is possible to overgeneralize from these results.…”

Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target

“…The potential for compensatory repair (developmental or pharmacological) is the primary focus of injury models of neurodevelopmental disorders, such as those resulting from inflammation or hypoxia-ischemia, that generally model an early single injury to the brain. In one such model, a developmental brain injury was produced by the premature delivery of rabbit kits resulting in altered arborisation of hippocampal neurons as well as reduced numbers of dendritic spines [ 173 ]. Oestrogen supplementation was provided to a subgroup of preterm born kits, which was found to ameliorate the spine pathology on the apical dendrites, in line with the hypothesis that reduced exposure to maternal oestrogen may be the cause of this neuropathology.…”

“…Oestrogen supplementation was provided to a subgroup of preterm born kits, which was found to ameliorate the spine pathology on the apical dendrites, in line with the hypothesis that reduced exposure to maternal oestrogen may be the cause of this neuropathology. Treatment with the TrkB agonist 7,8-dihydroxyflavone (DHF) was also able to ameliorate this apical spine pathology and both treatments also reduce anxiety-like behaviour in the offspring [ 173 ]. Interestingly, while reduced levels of Cdc42 and Rac proteins were identified in addition to the morphological changes produced by preterm birth, these were not ameliorated with oestrogen of DFH treatment, suggesting an alternative pathway was responsible of the spine pathology in this injury model.…”