Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons
Evelyn McClendon PhD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorKevin Chen BS
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorXi Gong MD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorElica Sharifnia BA
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorMatthew Hagen BA
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorVictor Cai
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorDaniel C. Shaver BA
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorArt Riddle PhD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorJustin M. Dean PhD
Department of Physiology, University of Auckland, Auckland, New Zealand
Search for more papers by this authorAlistair J. Gunn MBChB, PhD
Department of Physiology, University of Auckland, Auckland, New Zealand
Search for more papers by this authorClaudia Mohr PhD
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Search for more papers by this authorJoshua S. Kaplan BA
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Search for more papers by this authorDavid J. Rossi PhD
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Search for more papers by this authorChristopher D. Kroenke PhD
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR
Search for more papers by this authorA. Roger Hohimer PhD
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR
Search for more papers by this authorCorresponding Author
Stephen A. Back MD, PhD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Department of Neurology, Oregon Health and Science University, Portland, OR
Address correspondence to Dr Back, Oregon Health and Science University, Department of Pediatrics, Division of Pediatric Neuroscience, 3181 S.W. Sam Jackson Park Rd, Mail Code L481, Portland, OR 97239-3098. E-mail: [email protected]Search for more papers by this authorEvelyn McClendon PhD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorKevin Chen BS
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorXi Gong MD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorElica Sharifnia BA
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorMatthew Hagen BA
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorVictor Cai
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorDaniel C. Shaver BA
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorArt Riddle PhD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Search for more papers by this authorJustin M. Dean PhD
Department of Physiology, University of Auckland, Auckland, New Zealand
Search for more papers by this authorAlistair J. Gunn MBChB, PhD
Department of Physiology, University of Auckland, Auckland, New Zealand
Search for more papers by this authorClaudia Mohr PhD
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Search for more papers by this authorJoshua S. Kaplan BA
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Search for more papers by this authorDavid J. Rossi PhD
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Search for more papers by this authorChristopher D. Kroenke PhD
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR
Advanced Imaging Research Center, Oregon Health and Science University, Portland, OR
Search for more papers by this authorA. Roger Hohimer PhD
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR
Search for more papers by this authorCorresponding Author
Stephen A. Back MD, PhD
Department of Pediatrics, Oregon Health and Science University, Portland, OR
Department of Neurology, Oregon Health and Science University, Portland, OR
Address correspondence to Dr Back, Oregon Health and Science University, Department of Pediatrics, Division of Pediatric Neuroscience, 3181 S.W. Sam Jackson Park Rd, Mail Code L481, Portland, OR 97239-3098. E-mail: [email protected]Search for more papers by this authorAbstract
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 4 weeks after HI. Patch-clamp 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. Nor 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. Ann Neurol 2014;75:508–524
Supporting Information
Additional Supporting Information can be found in the online version of this article.
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| ana24100-sup-0001-suppfig1.tif7.6 MB | Supporting Information Figure 1. |
| ana24100-sup-0002-suppfig2.tif1.4 MB | Supporting Information Figure 2. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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