GluN2A-/- Mice Lack Bidirectional Synaptic Plasticity in the Dentate Gyrus and Perform Poorly on Spatial Pattern Separation Tasks.

The different secondary subunits of the N-methyl-d-aspartate (NMDA) receptor each convey unique biophysical properties to the receptor complex, and may be key in determining the functional role played by NMDA receptors. In the hippocampus, the GluN2A and GluN2B subunits are particularly abundant; however, their exact roles in synaptic plasticity and behavior remain controversial. Here, we show that mice carrying a deletion for the GluN2A subunit (GluN2A(-/-)) demonstrate a severely compromised NMDA to AMPA receptor current ratio in granule cells from the dentate gyrus (DG), while granule cell morphology is unaltered. This deficit is accompanied by significant impairments in both LTP and LTD in the DG, whereas only minor impairments are observed in the CA1. In accordance with these hippocampal region-specific deficits, GluN2A(-/-) mice show impaired performance on the DG-associated task of spatial pattern separation. In contrast, GluN2A(-/-) mice show no deficit in temporal pattern separation, a process associated with CA1 functioning. Thus, our results establish the GluN2A subunit as a significant contributor to both bidirectional synaptic plasticity and spatial pattern separation in the DG.

Differential response of hippocampal subregions to stress and learning.

The hippocampus has two functionally distinct subregions-the dorsal portion, primarily associated with spatial navigation, and the ventral portion, primarily associated with anxiety. In a prior study of chronic unpredictable stress (CUS) in rodents, we found that it selectively enhanced cellular plasticity in the dorsal hippocampal subregion while negatively impacting it in the ventral. In the present study, we determined whether this adaptive plasticity in the dorsal subregion would confer CUS rats an advantage in a spatial task-the radial arm water maze (RAWM). RAWM exposure is both stressful and requires spatial navigation, and therefore places demands simultaneously upon both hippocampal subregions. Therefore, we used Western blotting to investigate differential expression of plasticity-associated proteins (brain derived neurotrophic factor [BDNF], proBDNF and postsynaptic density-95 [PSD-95]) in the dorsal and ventral subregions following RAWM exposure. Lastly, we used unbiased stereology to compare the effects of CUS on proliferation, survival and neuronal differentiation of cells in the dorsal and ventral hippocampal subregions. We found that CUS and exposure to the RAWM both increased corticosterone, indicating that both are stressful; nevertheless, CUS animals had significantly better long-term spatial memory. We also observed a subregion-specific pattern of protein expression following RAWM, with proBDNF increased in the dorsal and decreased in the ventral subregion, while PSD-95 was selectively upregulated in the ventral. Finally, consistent with our previous study, we found that CUS most negatively affected neurogenesis in the ventral (compared to the dorsal) subregion. Taken together, our data support a dual role for the hippocampus in stressful experiences, with the more resilient dorsal portion undergoing adaptive plasticity (perhaps to facilitate escape from or neutralization of the stressor), and the ventral portion involved in affective responses.

Clopidogrel loading dose and bleeding outcomes in patients undergoing urgent coronary artery bypass grafting.

BACKGROUND: Coronary artery bypass grafting (CABG) performed within 5 days of clopidogrel administration is associated with increased bleeding. The impact of clopidogrel loading dose is unknown. We examined the effect of clopidogrel loading dose on bleeding outcomes in patients undergoing urgent CABG. METHODS: Clinical outcomes were examined retrospectively for 196 consecutive patients undergoing urgent CABG within 5 days of a clopidogrel loading dose between January 2003 and June 2009. Major bleeding was defined as a fall in hemoglobin > 5 g/dL, fatal or intracranial bleeding, or cardiac tamponade. RESULTS: One hundred forty-eight patients received 300 mg and 48 patients received ≥ 600 mg clopidogrel loading. Patients were predominantly male (78%) with a mean age of 66 ± 10 years. Mean duration from clopidogrel loading to CABG was 3.0 ± 1.5 and 3.0 ± 1.6 days for the 300 and 600 mg loading doses, respectively. Major bleeding occurred in 47% of patients receiving 300 mg and 73% of patients receiving ≥ 600 mg clopidogrel loading (P = .002). Compared with 300 mg, patients receiving ≥ 600 mg had greater 24-hour chest tube output (391 ± 251 vs 536 ± 354 mL, P = .01), stayed longer in surgical intensive care (4.3 ± 4.1 vs 5.0 ± 3.1 days, P = .0001), and trended toward greater reoperation for bleeding (5% vs 12%, P = .09). Following multivariate analysis, clopidogrel loading dose ≥ 600 mg (odds ratio 2.8, CI 1.2-6.6), preoperative hemoglobin (3.4, 2.7-5.0 per 1 g/dL increase), and female gender (2.9, 1.1-7.4) predicted major bleeding. CONCLUSIONS: Higher clopidogrel loading doses are associated with increased bleeding when administered within 5 days of CABG. The development of shorter-acting, reversible, oral antiplatelet agents may reduce perioperative bleeding in this population.