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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Prenatal Hypoxia-Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression
Lauren L Jantzie1, Paulina M Getsy2, Jesse L Denson3
1Department of Pediatrics, University of New Mexico , Albuquerque, NM , USA ; Department of Neurosciences, University of New Mexico , Albuquerque, NM , USA ; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School , Boston, MA , USA ; Department of Neurology, Boston Children's Hospital, Harvard Medical School , Boston, MA , USA.
Insights
Prenatal brain injury impairs KCC2 development, disrupting inhibitory neural circuits. This early disruption in GABAergic signaling contributes to long-term neurological deficits, including epilepsy and cognitive impairment.
Area of Science:
- Neuroscience
- Developmental Biology
- Perinatal Medicine
Background:
- Perinatal brain injury leads to chronic neurological deficits, hindering independence in affected children.
- Cerebral function relies on balanced excitation and inhibition during neural circuit development.
- Early GABAergic responses are excitatory, becoming inhibitory postnatally via KCC2 upregulation.
Purpose of the Study:
- To investigate if prenatal hypoxic-ischemic brain injury chronically impairs KCC2 developmental upregulation.
- To determine the impact of impaired KCC2 on hippocampal microstructural integrity and inhibitory tone.
Main Methods:
- Utilized a rat model of late-gestation hypoxia-ischemia (HI).
- Employed diffusion tensor imaging to assess hippocampal microstructure.
- Measured KCC2 expression and inhibitory post-synaptic currents in the CA3 subfield.
Main Results:
- HI resulted in poor hippocampal CA3 microstructural integrity (reduced FA, elevated RD).
- Reduced KCC2 expression (protein and on neurons) was observed in the CA3 subfield.
- Prenatal HI led to decreased inhibitory post-synaptic currents, impairing hippocampal CA3 inhibitory tone.
Conclusions:
- Prenatal transient HI impairs the critical developmental upregulation of KCC2 in the hippocampus.
- This failure to establish timely inhibitory tone contributes to a lower seizure threshold and cognitive impairments.
- Findings highlight KCC2's crucial role in preventing long-term neurological sequelae from perinatal brain injury.
Abstract:
Infants who suffer perinatal brain injury, including those with encephalopathy of prematurity, are prone to chronic neurological deficits, including epilepsy, cognitive impairment, and behavioral problems, such as anxiety, inattention, and poor social interaction. These deficits, especially in combination, pose the greatest hindrance to these children becoming independent adults. Cerebral function depends on adequate development of essential inhibitory neural circuits and the appropriate amount of excitation and inhibition at specific stages of maturation. Early neuronal synaptic responses to γ-amino butyric acid (GABA) are initially excitatory. During the early postnatal period, GABAAR responses switch to inhibitory with the upregulation of potassium-chloride co-transporter KCC2. With extrusion of chloride by KCC2, the Cl(-) reversal potential shifts and GABA and glycine responses become inhibitory. We hypothesized that prenatal hypoxic-ischemic brain injury chronically impairs the developmental upregulation of KCC2 that is essential for cerebral circuit formation. Following late gestation hypoxia-ischemia (HI), diffusion tensor imaging in juvenile rats shows poor microstructural integrity in the hippocampal CA3 subfield, with reduced fractional anisotropy and elevated radial diffusivity. The loss of microstructure correlates with early reduced KCC2 expression on NeuN-positive pyramidal neurons, and decreased monomeric and oligomeric KCC2 protein expression in the CA3 subfield. Together with decreased inhibitory post-synaptic currents during a critical window of development, we document for the first time that prenatal transient systemic HI in rats impairs hippocampal CA3 inhibitory tone. Failure of timely development of inhibitory tone likely contributes to a lower seizure threshold and impaired cognitive function in children who suffer perinatal brain injury.
