Long term treatment with the GABA uptake inhibitor, NO-05-0328, ameliorates loss of hippocampal CA1 pyramidal cells after cerebral ischemia in the rat

The α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinoxaline (NBQX), offers protection to hippocampal CA1 pyramidal cells after short episodes of transient cerebral ischemia. Besides CA1 pyramidal cells, neurons containing somatostatin (SS) and located in the dentate hilus of the hippocampal formation are lost after cerebral ischemia. We studied the protective effects of NBQX on SS neurons in the hilus and on hippocampal CA1 pyramidal cells following 8, 10, or 12 min of four-vessel occlusion ischemia during systemic hypotension. NBQX was administered 3 × 30 mg/kg at 0, 10, and 25 after induction of ischemia or sham, and all rats survived for 7 days. NBQX given to control rats without ischemia had no influence on number or morphology of hilar SS neurons and CA1 pyramidal cells. After 8 min of ischemia, NBQX prevented loss of hilar SS neurons. After 10 and 12 min of ischemia, NBQX had no significant effects on loss of SS neurons in the dentate hilus. However, in all ischemic groups, NBQX significantly reduced loss of CA1 pyramidal cells as compared to control rats. This neuroprotective effect decreased gradually and significantly as the time of ischemia increased. Our results support the observation that SS neurons in hilus are among the most ischemia-vulnerable neurons in the brain. We found that administration of NBQX in generally accepted dosages can protect the rapidly dying SS neurons in hilus from only brief episodes of ischemia.

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Long-term potentiation at single fiber inputs to hippocampal CA1 pyramidal cells.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.93.16.8710 ◽

1996 ◽

Vol 93 (16) ◽

pp. 8710-8715 ◽

Cited By ~ 76

Author(s):

J. T. Isaac ◽

G. O. Hjelmstad ◽

R. A. Nicoll ◽

R. C. Malenka

Keyword(s):

Pyramidal Cells ◽

Long Term Potentiation ◽

Single Fiber ◽

Ca1 Pyramidal Cells ◽

Term Potentiation ◽

Hippocampal Ca1

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Chronic nicotine-induced switch in Src-family kinase signaling for long-term potentiation induction in hippocampal CA1 pyramidal cells

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2006.05213.x ◽

2006 ◽

Vol 24 (11) ◽

pp. 3271-3284 ◽

Cited By ~ 9

Author(s):

Yoshihiko Yamazaki ◽

Yousheng Jia ◽

Jamie K. Wong ◽

Katumi Sumikawa

Keyword(s):

Pyramidal Cells ◽

Long Term Potentiation ◽

Kinase Signaling ◽

Src Family Kinase ◽

Chronic Nicotine ◽

Ca1 Pyramidal Cells ◽

Term Potentiation ◽

Hippocampal Ca1

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Impairment of Hippocampal CA1 Heterosynaptic Transformation and Spatial Memory by β-Amyloid25–35

Journal of Neurophysiology ◽

10.1152/jn.00230.2001 ◽

2002 ◽

Vol 87 (5) ◽

pp. 2441-2449 ◽

Cited By ~ 38

Author(s):

Miao-Kun Sun ◽

Daniel L. Alkon

Keyword(s):

Cognitive Impairment ◽

Spatial Memory ◽

Active Form ◽

Pyramidal Cells ◽

Single Pulse ◽

Memory Impairments ◽

Ca1 Pyramidal Cells ◽

Synaptic Modification ◽

Hippocampal Ca1

In Alzheimer's disease, the cholinergic damage (reduced neurotransmission) and cognitive impairment occur long before β-amyloid (Aβ) plaque formation. It has not been established whether the link between soluble Aβ and cholinergic functions contributes to synaptic dysfunction that underlies the cognitive impairment. Here, we report that Aβ25–35, an active form of Aβ, inhibited long-term synaptic modification that depends on the associative activation of cholinergic and GABAergic inputs when bilaterally injected intracerebroventricularly (icv; 200 μg/site). The Aβ microinjections did not affect single-pulse–evoked glutamatergic and GABAergic synaptic transmission onto the hippocampal CA1 pyramidal cells, while cholinergic intracellular θ was dramatically reduced by the Aβ25–35 injection. Spatial memory of the water maze task was also impaired by the bilateral icv Aβ25–35 injections, while bilateral microinjections of the same dose of Aβ35–25was ineffective in affecting the long-term synaptic modification evoked by associative activation of cholinergic and GABAergic inputs, the cholinergic intracellular θ, or producing memory impairments. Thus restoring the synaptic plasticity involved in this associative activation of cholinergic and GABAergic inputs may offer an important therapeutic target in the treatment of early Aβ-induced memory decline.

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