Involvement of glycine binding site of NMDA receptor in the prefrontal cortex of SHRSP/Ezo as an AD/HD animal model

[Speaker] Hiroki Shikanai:1
[Co-author] Nobuhiro Oshima:2, Hidekazu Kawashima:2, Shin-Ichi Kimura:1, Sachiko Hiraide:1, Kenji Iizuka:1, Takeshi Izumi:1
1:Department of Pharmacology, Health Science University of Hokkaido, Japan, 2:Department of Biophysical Sciences, Health Science University of Hokkaido, Japan

Background: Attention deficit/ hyperactivity disorder (AD/HD) is a mild developmental disorder. We previously reported that stroke-prone spontaneously hypertensive rat/Ezo (SHRSP/Ezo) had high validity as an AD/HD animal model, because of its behavioral phenotype. It was reported that AD/HD had the front-cortical dysfunction, hypofrontality. Based on these reports, we hypothesized that SHRSP/Ezo as AD/HD animal model has some fronto-cortical incompetence. Thus, we evaluated the excitatory synaptic function in the PFC of SHRSP/Ezo using electrophysiological and pharmacological methods.
Methods: At 6 weeks old, SHRSP/Ezo and its genetic control, WKY/Ezo were anesthetized and immediately decapitated. Using acute coronal brain slice, we recorded excitatory postsynaptic potential (EPSP) in layer V pyramidal neurons in the PFC by whole-cell patch clamp recording method to assess synaptic plasticity in the form of long-term potentiation (LTP). We also performed N-methyl-D-aspartic acid (NMDA) receptor binding assay in the PFC and hippocampus with radio-labeled NMDA receptor antagonist [3H]MK-801 using homogenized membrane tissue.
Results: Theta burst stimulation induced long-lasting EPSP enhancement, LTP, in the PFC of WKY/Ezo, whereas failed to induce LTP, in that of SHRSP/Ezo. The Kd value of [3H]MK-801 binding for NMDA receptors in the PFC of SHRSP/Ezo was higher than in the WKY/Ezo. Neither the Bmax nor Kd of [3H]MK-801 binding in the SHRSP/Ezo hippocampus were significantly different to WKY/Ezo. When we added 100 μM glycine into the incubate solution to assess the function of glycine binding site of NMDA receptor in each rat, there was no significant difference of Kd value in the PFC of SHRSP/Ezo.
Conclusion: These results suggest that the AD/HD animal model SHRSP/Ezo has NMDA receptor dysfunction in the PFC, but not the hippocampus. Moreover, some ligands for glycine binding site in NMDA receptor can be a possibility of new drug for AD/HD treatment.

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