Related Experiment Video
Updated: Aug 30, 2026
Hypoxia Alters miRNAs Levels Involved in Non-Mendelian Inheritance of Autism Spectrum Disorder in Mice
Published on: July 11, 2025
Neonatal hypoxia-ischemia differentially upregulates MAGUKs and associated proteins in PSD-93-deficient mouse brain
Xiangning Jiang1, Dezhi Mu, R Ann Sheldon
1Department of Neurology, University of California, San Francisco 94143-0663, USA.
Background And Purpose:
Postsynaptic density (PSD)-93 and PSD-95 are the major membrane-associated guanylate kinases (MAGUKs) at excitatory synapses of the brain linking the N-methyl-d-aspartate receptor (NMDAR) with neuronal nitric oxide synthase (nNOS), which contributes to cell death after neonatal hypoxia-ischemia (HI). We investigated whether deletion of PSD-93 would dissociate the NMDAR from nNOS and be neuroprotective.
Methods:
Postnatal day 7 wild-type (+/+), heterozygous (+/-), and homozygous (-/-) PSD-93 knockout mice were subjected to HI by permanent ligation of the right carotid artery, followed by exposure to 8% O2/92% N2 for 1 hour. Brains were scored 5 days later for damage with cresyl violet and iron stains. Western blot and coimmunoprecipitation were used to determine the expression and association of the major PSD proteins.
Results:
There was no significant difference between PSD-93 (-/-) and (+/+) mice in mortality or degree of brain injury. In the absence of PSD-93, PSD-95 still interacted with NR2B and nNOS. Under physiological conditions, PSD-95, nNOS, NR2A, and NR2B were unaltered in the (-/-) pups. However, at 24 hours after HI, protein expression of PSD-95, nNOS, and NR2A but not NR2B was markedly higher in the (-/-) than in the (+/+) pups. In (+/+) pups, HI resulted in decreased expression of NR2A but not NR2B in cortex and decreased NR2A and NR2B expression in hippocampus, but this reduction was not observed in (-/-) pups.
Conclusions:
PSD-93 is not essential for baseline synaptic function but may participate in regulation of NMDAR-associated signaling pathways after HI injury. Deletion of PSD-93 alone does not provide neuroprotection after neonatal HI, possibly a result, in part, of upregulation of PSD-95. MAGUKs may substitute for one another, allowing normal NMDAR function in the postnatal period.
Insights
Deleting PSD-93 (postsynaptic density-93) did not protect against neonatal brain injury, possibly due to PSD-95 (postsynaptic density-95) upregulation. These MAGUKs may compensate for each other.
Area of Science:
- Neuroscience
- Synaptic Plasticity
- Neuroprotection
Background:
- Postsynaptic density (PSD)-93 and PSD-95 are key membrane-associated guanylate kinases (MAGUKs) in excitatory synapses.
- These proteins link N-methyl-d-aspartate receptors (NMDARs) with neuronal nitric oxide synthase (nNOS), impacting cell death after neonatal hypoxia-ischemia (HI).
Purpose of the Study:
- To investigate if PSD-93 deletion dissociates NMDAR from nNOS.
- To determine if PSD-93 knockout confers neuroprotection against neonatal HI.
Main Methods:
- Utilized PSD-93 knockout (PSD-93-/-) and wild-type (+/+) mice subjected to neonatal HI.
- Assessed brain damage using cresyl violet and iron stains.
- Employed Western blot and coimmunoprecipitation to analyze protein expression and interactions.
Main Results:
- No significant difference in mortality or brain injury between PSD-93-/- and +/+ mice.
- PSD-95 maintained interaction with NR2B and nNOS in PSD-93 deficient mice.
- Post-HI, PSD-93-/- mice showed increased PSD-95, nNOS, and NR2A expression compared to controls, with preserved NR2A/NR2B levels.
Conclusions:
- PSD-93 is not essential for baseline synaptic function but may regulate NMDAR signaling post-HI.
- PSD-93 deletion alone does not provide neuroprotection, potentially due to PSD-95 upregulation.
- MAGUKs may exhibit functional redundancy, ensuring normal NMDAR function postnatally.
