Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons

In addition to cerebral palsy, preterm survivors are at risk for a wide range of disabilities that include minor motor dysfunction and disturbances in learning, cognition, visual integration, language processing, attention and socialization.1 Whereas these diverse disabilities were previously attributed principally to cerebral white matter injury (WMI), disrupted gray matter development increasingly appears to contribute to the global developmental disabilities that occur in 25–50% of preterm survivors.2 Several large human neuroimaging studies have identified significant reductions in the growth of cortical and subcortical gray matter structures that include the basal ganglia, thalamus and hippocampus.3 The major cellular mechanisms related to gray matter volume loss in contemporary populations of preterm survivors remain controversial. Several human autopsy studies of cases with significant periventricular leukomalacia (PVL) found widespread loss of neurons in the cortex, subplate and thalamus.4–6 Neuronal loss was attributed to retrograde neuroaxonal degeneration related to PVL and to direct deletion of neurons, particularly GABAergic interneurons that appear to migrate through human white matter during the period of high risk for WMI.7, 8 An alternative mechanism is supported by recent human neuroimaging studies that identified aberrant cortical development in preterm survivors with minimal PVL. These studies found that the normal progressive loss of cortical anisotropy was delayed;9, 10 consistent with our recent preclinical studies that related delayed loss of cortical anisotropy to widespread arrested maturation of the dendritic arbor of cortical projection neurons.11 To further define the pathogenesis of gray matter mal-development, we have employed an in utero model of preterm ovine global cerebral HI that closely reproduces the spectrum of cerebral injury observed in preterm human infants.12 The majority of animals acquire moderate diffuse WMI without the pronounced white matter necrosis that now occurs in only a small minority of human preterm survivors.13 Notably, these animals also display progressive cortical volume loss that occurs without significant neuronal loss.11 Rather, volume loss arises from reduced complexity of the dendritic arbor of pyramidal neurons, which comprise the major population of cortical projection neurons. Hence, the response of some populations of immature cortical neurons appears to be biased towards dysmaturation rather than cell death, and may be related to the severity of cerebral HI. Here we tested the hypothesis that the neuronal dysmaturation observed in response to preterm global cerebral HI is not limited to the cerebral cortex, but also more diffusely disrupts maturation of other populations of projection neurons in subcortical gray matter. We specifically analyzed the caudate nucleus (CN), which displays reduced growth in human preterm survivors14, 15 and has been associated with multiple neurobehavioral disturbances. These include minor motor impairment,16 disturbances in IQ,16 attention,17 visual-perceptual learning18 and executive function.19 In response to HI, we found a significant reduction in caudate volume. Impaired caudate growth was not consistent with a loss of either GABAergic projection neurons or interneurons. Rather, impaired caudate growth was accompanied by diffuse reductions in the maturation of the basal dendritic arbor of medium spiny neurons (MSNs), which comprise the major efferent projections of the CN. Disturbances in connectivity were supported by a significant reduction in the number of dendritic spines of MSNs as well as functional disturbances in glutamatergic synaptic transmission.