Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons

Abstract

Objective Recently we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry and Golgi staining defined CN growth, cell death, proliferation and dendritic maturation in preterm fetal sheep four weeks after HI. Patch-clamping recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Neither was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity.

Early Environmental Enrichment Enhances Abnormal Brain Connectivity in a Rabbit Model of Intrauterine Growth Restriction

“…Both DSs and PNNs have been involved in the regulation of synaptic connectivity and plasticity [43][44][45][46]. Our results showing decreased DS levels in IUGR rabbits are in line with previously described studies on guinea pig and sheep model showing changes in DS density and morphology along with changes in synaptic receptors after acute and chronic intrauterine insults [16,[47][48][49]. On the contrary, although there is growing interest in the description of PNN alterations related to specific brain diseases such as Alzheimer disease, schizophrenia, and epilepsy [45,50], the pattern of alterations in the PNNs related to IUGR had not been previously evaluated.…”

Brain Injury in the Preterm Infant: New Horizons for Pathogenesis and Prevention

“…106 However, reduced growth of the caudate was not explained by loss of GABAergic interneurons or projection neurons. Reduced growth of the cerebral cortex and the caudate was also not related to loss of cortical pyramidal neurons 107 or medium spiny projection neurons in the caudate, 108 which comprise the majority of neurons in each region.…”

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

“…In addition to the previously reported mechanisms, including impairments of various cellular components, such as the dendritic arbor and synapse formation of neurons, and myelination failure (9,13,15), defective neuronal alignment is presumed to be another mechanism underlying the later development of cognitive impairment in the extremely preterm infants. Neuronal migration and alignment may also be affected in other brain regions besides the neocortex.…”

“…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).…”

“…Until recently, it was considered that rat E21 (the last day of pregnancy) corresponds to human gestational weeks (GWs) [15][16] and that, in the human brains, neurogenesis is completed by the end of the 16th week (18,19); thus, the prevailing rat model of perinatal hypoxic-ischemic brain injury uses postnatal pups in which neurogenesis has been completed (20). However, recent findings indicate that human neocortical neurogenesis continues into the third trimester (21,22), suggesting continuation of neuronal migration following neurogenesis even after 23 GWs, the gestational week at which extremely preterm infants have live births.…”