Prenatal Exposure to the CB1 Receptor Agonist WIN 55,212-2 Causes Learning Disruption Associated with Impaired Cortical NMDA Receptor Function and Emotional Reactivity Changes in Rat Offspring

Background:Previously we showed that 6-hydroxydopamine lesions of the substantia nigra eliminate corticostriatal LTP and that the neuroimmunolophilin ligand (NIL), GPI-1046, restores LTP.Methods:We used cDNA microarrays to determine what mRNAs may be over- or under-expressed in response to lesioning and/or GPI-1046 treatment. Patch clamp recordings were performed to investigate changes in NMDA channel function before and after treatments.Results:We found that 51 gene products were differentially expressed. Among these we found that GPI-1046 treatment up-regulated presenilin-1 (PS-1) mRNA abundance. This finding was confirmed using QPCR. PS-1 protein was also shown to be over-expressed in the striatum of lesioned/GPI-1046-treated rats. As PS-1 has been implicated in controlling NMDA-receptor function and LTP is reduced by lesioning we assayed NMDA mediated synaptic activity in striatal brain slices. The lesion-induced reduction of dopaminergic innervation was accompanied by the near complete loss of NDMA receptor-mediated synaptic transmission between the cortex and striatum. GPI-1046 treatment of the lesioned rats restored NMDA-mediated synaptic transmission but not the dopaminergic innervation. Restoration of NDMA channel function was apparently specific as the sodium channel current density was also reduced due to lesioning but GPI-1046 did not reverse this effect. We also found that restoration of NMDA receptor function was also not associated with either an increase in NMDA receptor mRNA or protein expression.Conclusion:As it has been previously shown that PS-1 is critical for normal NMDA receptor function, our data suggest that the improvement of excitatory neurotransmission occurs through the GPI-1046-induced up-regulation of PS-1.

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Control of NMDA Receptor Function by the NR2 Subunit Amino-Terminal Domain

Journal of Neuroscience ◽

10.1523/jneurosci.1365-09.2009 ◽

2009 ◽

Vol 29 (39) ◽

pp. 12045-12058 ◽

Cited By ~ 137

Author(s):

H. Yuan ◽

K. B. Hansen ◽

K. M. Vance ◽

K. K. Ogden ◽

S. F. Traynelis

Keyword(s):

Nmda Receptor ◽

Receptor Function ◽

Amino Terminal ◽

Terminal Domain ◽

Nmda Receptor Function ◽

Amino Terminal Domain

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Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory

Neurobiology of Disease ◽

10.1016/j.nbd.2008.04.011 ◽

2008 ◽

Vol 31 (2) ◽

pp. 250-260 ◽

Cited By ~ 115

Author(s):

Chanel J. Taylor ◽

David R. Ireland ◽

Irene Ballagh ◽

Katie Bourne ◽

Nicola M. Marechal ◽

...

Keyword(s):

Nmda Receptor ◽

Spatial Memory ◽

Amyloid Precursor Protein ◽

Long Term Potentiation ◽

Precursor Protein ◽

Receptor Function ◽

Term Potentiation ◽

Nmda Receptor Function

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Long-Lasting Alterations in Gene Expression of Postsynaptic Density 95 and Inotropic Glutamatergic Receptor Subunit in the Mesocorticolimbic System of Rat Offspring Born to Morphine-Addicted Mothers

BioMed Research International ◽

10.1155/2018/5437092 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Pei-Ling Wu ◽

Yung-Ning Yang ◽

Jau-Ling Suen ◽

Yu-Chen S. H. Yang ◽

Chun-Hwa Yang ◽

...

Keyword(s):

Gene Expression ◽

Nmda Receptor ◽

Glutamate Receptor ◽

Ampa Receptor ◽

Prenatal Exposure ◽

Molecular Mechanisms ◽

Postsynaptic Density ◽

Receptor Subunit ◽

Rat Offspring ◽

Ampa Receptor Subunit

Prenatal exposure to morphine causes altered glutamatergic neurotransmission, which plays an important pathophysiological role for neurobiological basis of opiate-mediated behaviors in such offspring. However, it is still not clear whether such alteration involves gene expression of ionotropic glutamate receptor subunits. In this study, we further studied whether prenatal morphine exposure resulted in long-term changes in the gene expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, N-methyl-d-aspartate (NMDA) receptor, and postsynaptic density 95 in the mesocorticolimbic area (an essential integration circuitry for drug craving behavior), nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC), of rat offspring from morphine-addicted mothers. Experimental results showed that prenatal morphine exposure led to a persistent downregulation of gene expression in the AMPA and NMDA receptor subunit, with a differential manner of decreased magnitudes, at the age of postnatal days 14 (P14) and P30. However, in PFC, the gene expression of the AMPA receptor subunit was not synchronized in observed rat offspring subjected to prenatal morphine exposure. An upregulation of gene expression in the AMPA receptor subunit 3 (GluR3) was persistently observed at P14 and P30. Furthermore, the gene expressions of PSD-95 in NAc, VTA, and PFC were all decreased concurrently. Collectively, the results suggest that prenatal exposure to morphine may initiate molecular mechanisms leading to a long-lasting, differential alteration in gene expression of the inotropic glutamate receptor subunit and PSD-95 in the mesocorticolimbic circuitry in rat offspring. This study raises a possibility in which differential changes in gene expression with a long-lasting manner may play a role for the development of nearly permanent changes in opiate-mediated behaviors, at least in part for the neurobiological pathogenesis in offspring.

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