Impaired expression of postsynaptic density proteins in the hippocampal CA1 region of rats following perinatal hypoxia.
Perinatal hypoxia is an important cause of brain injury amongst the newborn, such injury often resulting in an increased risk of impaired performance as regards learning and memory in later life for the affected individual. The postsynaptic density 95 (PSD-95) protein is a cytoskeletal specialization involved in the anchoring of N-methyl-d-aspartate (NMDA) receptors in postsynaptic neurons and has been reported to serve several important functions (e.g., synaptogenesis, synaptic plasticity and learning and memory performance) for the mammalian brain. Herein we investigated the long-term effects of perinatal hypoxia upon the complex of PSD-95 with NMDAR subunits by means of downstream signalling cAMP response element binding protein (CREB) phosphorylation at the Serine-133 locus (CREB(Ser-133) phosphorylation) within the hippocampal CA1 area (an essential integration area for mammalian learning and memory) within test-rat brains, as well as the effects upon afflicted-individual long-term learning and memory performance. We also assessed the therapeutic efficacy of dopamine D1/D5 receptor (D1/D5R) activation for such study animals. Perinatal hypoxia on postnatal day ten (P10) led to impaired performance as regards long-term spatial learning and memory (as determined on P45) associated with decreases in the level of CREB(Ser-133) phosphorylation and decreases in the expression of the complex of PSD-95 with NMDAR subunits (NR1, NR2A, and NR2B). In addition, activation of the D1/D5R via A68930 (a selective, CNS-permeable agonist of D1/D5Rs) administration (2 mg/kg/day, P17-23 inclusively) markedly attenuated the hypoxia-induced deleterious effects, suggesting an effective therapeutic efficacy for A68930. Our results demonstrate the long-term effects of perinatal hypoxia upon the developing brain and provide additional insights into the relative vulnerability of postsynaptic density (PSD) proteins to such insult, as well as the impairment of downstream transcription signalling CREB(Ser-133) phosphorylation following perinatal hypoxia. More importantly, D1/D5R activation following perinatal hypoxia may be an alternative therapeutic strategy to that which is currently available and may offer significant clinical potential for hypoxia sufferers.
Chen
Wu-Fu
WF
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Chang
Hung
H
Wong
Chih-Shung
CS
Huang
Li-Tung
LT
Yang
Chin-Hwa
CH
Yang
San-Nan
SN
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005311:Fetal Hypoxia / Q000378:metabolism* / Q000523:psychology; D006624:Hippocampus / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism* / Q000523:psychology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018782:Maze Learning; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D050641:Receptors, Dopamine D5 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine; D013550:Swimming; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D050641:Receptors, Dopamine D5; D012694:Serine