Selective vulnerability of hippocampal cornu ammonis 1 pyramidal cells to excitotoxic insult is associated with the expression of polyamine-sensitive N-methyl-d-asparate-type glutamate receptors

Abstract

Excess glutamate release and stimulation of post-synaptic glutamatergic receptors have been implicated in the pathophysiology of many neurological diseases. The hippocampus, and the pyramidal cell layer of the cornu ammonus 1 (CA1) region in particular, has been noted for its selective sensitivity to excitotoxic insults. The current studies examined the role of N-methyl-Daspartate (NMDA) receptor subunit composition and sensitivity to stimulatory effects of the polyamine spermidine, an allosteric modulator of NMDA NR2 subunit activity, in hippocampal CA1 region sensitivity to excitotoxic insult. Organotypic hippocampal slice cultures of 8 day-old neonatal rat were obtained and maintained in vitro for 5 days. At this time, immunohistochemical analysis of mature neuron density (NeuN); microtubule associated protein-2(a,b) density (MAP-2); and NMDA receptor NR1 and NR2B subunit density in the primary cell layers of the dentate gyrus (DG), CA3, and CA1 regions, was conducted. Further, autoradiographic analysis of NMDA receptor distribution and density (i.e. [ 125 I]MK-801 binding) and spermidine (100 μM)-potentiated [ 125 I]MK-801 binding in the primary cell layers of these regions was examined. A final series of studies examined effects of prolonged exposure to NMDA (0.1-10 μM) on neurodegeneration in the primary cell layers of the DG, CA3, and CA1 regions, in the absence and presence of spermidine (100 μM) or ifenprodil (100 μM), an allosteric inhibitor of NR2B polypeptide subunit activity. The pyramidal cell layer of the CA1 region demonstrated significantly greater density of mature neurons, MAP-2, NR1 and NR2B subunits, and [ 125 I]MK-801 binding than the CA3 region or DG. Twenty-four hour NMDA (10 μM) exposure produced marked neurodegeneration (~350% of control cultures) in the CA1 pyramidal cell region that was significantly reduced by co-exposure to ifenprodil or APV. The Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 January 20. This neurodegeneration was markedly reduced with co-exposure to ifenprodil. These data suggest that selective sensitivity of the CA1 region to excitotoxic stimuli may be attributable to the density of mature neurons expressing polyamine-sensitive NR2B polypeptide subunits.

Hypoglycemia-induced alterations in hippocampal intrinsic rhythms: Decreased inhibition, increased excitation, seizures and spreading depression

“…We suggest that the CA1 increased susceptibility to SD and synaptic failure with hypoglycemia is likely related to the inherent higher expression of NMDA receptors in the postsynaptic densities and extrasynaptic membrane of the CA1 cells as compared to CA3 cells (Butler et al, 2010;Stanika et al, 2010;Tasker et al, 1992). This "excess" of NMDA receptors is activated by the hypoglycemic-mediated increase in glutamate and aspartate (Sandberg et al, 1986).…”

Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

“…D2DRs may exert protective effects against aging-related processes, such as neuroinflammation (64) and excitotoxicity in hippocampal neurons (65)(66)(67)(68)(69)(70). Excitotoxicity is particularly detrimental for hippocampal neurons, possibly due to the high density of glutamatergic synapses (71)(72)(73). Relatedly, hippocampal/temporal lobe D2DRs are reduced in pathological conditions such as Alzheimer's disease, and are correlated with cognitive deficits in these patients (74)(75)(76).…”

Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia

“…Numerous factors contribute to the CA1 susceptibility in ischemic insult, such as the density of NMDA receptors [37]; MAP-2, NR1 and NR2B subunits binding [38]; ATP-sensitive potassium channel [39]; and Na + -K + ATPase activity [40]. Interestingly, the mitochondrial function in the hippocampus regions also shows differences before and after cerebral ischemia.…”