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Age-related alterations in the expression of genes and synaptic plasticity associated with nitric oxide signaling in the mouse dorsal striatum.

Chepkova AN, Schönfeld S, Sergeeva OA - Neural Plast. (2015)

Bottom Line: A significant decrease in transcripts encoding neuronal nitric oxide (NO) synthase and receptors involved in its activation (NR1 subunit of the glutamate NMDA receptor and D1 dopamine receptor) was found in the striatum of old mice using gene array and real-time RT-PCR analysis.Corticostriatal NO-dependent LTD induced by pharmacological activation of group I metabotropic glutamate receptors underwent significant reduction with aging and could be restored by inhibition of cGMP hydrolysis indicating that its age-related deficit is caused by an altered NO-cGMP signaling cascade.It is suggested that age-related alterations in corticostriatal synaptic plasticity may result from functional alterations in receptor-activated signaling cascades associated with increasing neuroinflammation and a prooxidant state.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurophysiology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.

ABSTRACT
Age-related alterations in the expression of genes and corticostriatal synaptic plasticity were studied in the dorsal striatum of mice of four age groups from young (2-3 months old) to old (18-24 months of age) animals. A significant decrease in transcripts encoding neuronal nitric oxide (NO) synthase and receptors involved in its activation (NR1 subunit of the glutamate NMDA receptor and D1 dopamine receptor) was found in the striatum of old mice using gene array and real-time RT-PCR analysis. The old striatum showed also a significantly higher number of GFAP-expressing astrocytes and an increased expression of astroglial, inflammatory, and oxidative stress markers. Field potential recordings from striatal slices revealed age-related alterations in the magnitude and dynamics of electrically induced long-term depression (LTD) and significant enhancement of electrically induced long-term potentiation in the middle-aged striatum (6-7 and 12-13 months of age). Corticostriatal NO-dependent LTD induced by pharmacological activation of group I metabotropic glutamate receptors underwent significant reduction with aging and could be restored by inhibition of cGMP hydrolysis indicating that its age-related deficit is caused by an altered NO-cGMP signaling cascade. It is suggested that age-related alterations in corticostriatal synaptic plasticity may result from functional alterations in receptor-activated signaling cascades associated with increasing neuroinflammation and a prooxidant state.

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Age-related reduction of DHPG-LTD is reversed by the phosphodiesterase 5 inhibitor zaprinast (ZPRN). The time course of relative changes in field response amplitudes in corticostriatal slices from group II (a) and group III (b) mice after application of DHPG in the absence (DHPG) or presence of zaprinast (ZPRN + DHPG). Period of DHPG application is marked by open bar; ZPRN was applied 10 min before and together with DHPG (marked by filled bar). Significant differences between the DHPG-LTD magnitudes in the absence and presence of ZPRN are marked by asterisks, ***P < 0.001, t-test.
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fig7: Age-related reduction of DHPG-LTD is reversed by the phosphodiesterase 5 inhibitor zaprinast (ZPRN). The time course of relative changes in field response amplitudes in corticostriatal slices from group II (a) and group III (b) mice after application of DHPG in the absence (DHPG) or presence of zaprinast (ZPRN + DHPG). Period of DHPG application is marked by open bar; ZPRN was applied 10 min before and together with DHPG (marked by filled bar). Significant differences between the DHPG-LTD magnitudes in the absence and presence of ZPRN are marked by asterisks, ***P < 0.001, t-test.

Mentions: Studies on neurotoxic and transgenic rodent models of Parkinson's disease showed that inhibition of cGMP hydrolysis by the PDE5 inhibitor zaprinast is able to rescue corticostriatal HFS-LTD [37, 38]. In our previous study we also found that treatment with zaprinast restored both HFS-LTD and DHPG-LTD impaired by long exposure of corticostriatal slices to hyperammonemic conditions [39]. To test whether this inhibitor could reverse age-dependent reduction of DHPG-LTD we compared the effects of DHPG application in the absence and presence of zaprinast in slices from group II and group III mice. In both groups preapplication of zaprinast increased DHPG-LTD to the level characteristic of young animals (to 66 ± 3% and 64 ± 4% of baseline in group II (n = 8) and III (n = 9), resp.). The difference with the corresponding values of control DHPG-LTD for both groups is significant at P < 0.001 (Figure 7).


Age-related alterations in the expression of genes and synaptic plasticity associated with nitric oxide signaling in the mouse dorsal striatum.

Chepkova AN, Schönfeld S, Sergeeva OA - Neural Plast. (2015)

Age-related reduction of DHPG-LTD is reversed by the phosphodiesterase 5 inhibitor zaprinast (ZPRN). The time course of relative changes in field response amplitudes in corticostriatal slices from group II (a) and group III (b) mice after application of DHPG in the absence (DHPG) or presence of zaprinast (ZPRN + DHPG). Period of DHPG application is marked by open bar; ZPRN was applied 10 min before and together with DHPG (marked by filled bar). Significant differences between the DHPG-LTD magnitudes in the absence and presence of ZPRN are marked by asterisks, ***P < 0.001, t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4364378&req=5

fig7: Age-related reduction of DHPG-LTD is reversed by the phosphodiesterase 5 inhibitor zaprinast (ZPRN). The time course of relative changes in field response amplitudes in corticostriatal slices from group II (a) and group III (b) mice after application of DHPG in the absence (DHPG) or presence of zaprinast (ZPRN + DHPG). Period of DHPG application is marked by open bar; ZPRN was applied 10 min before and together with DHPG (marked by filled bar). Significant differences between the DHPG-LTD magnitudes in the absence and presence of ZPRN are marked by asterisks, ***P < 0.001, t-test.
Mentions: Studies on neurotoxic and transgenic rodent models of Parkinson's disease showed that inhibition of cGMP hydrolysis by the PDE5 inhibitor zaprinast is able to rescue corticostriatal HFS-LTD [37, 38]. In our previous study we also found that treatment with zaprinast restored both HFS-LTD and DHPG-LTD impaired by long exposure of corticostriatal slices to hyperammonemic conditions [39]. To test whether this inhibitor could reverse age-dependent reduction of DHPG-LTD we compared the effects of DHPG application in the absence and presence of zaprinast in slices from group II and group III mice. In both groups preapplication of zaprinast increased DHPG-LTD to the level characteristic of young animals (to 66 ± 3% and 64 ± 4% of baseline in group II (n = 8) and III (n = 9), resp.). The difference with the corresponding values of control DHPG-LTD for both groups is significant at P < 0.001 (Figure 7).

Bottom Line: A significant decrease in transcripts encoding neuronal nitric oxide (NO) synthase and receptors involved in its activation (NR1 subunit of the glutamate NMDA receptor and D1 dopamine receptor) was found in the striatum of old mice using gene array and real-time RT-PCR analysis.Corticostriatal NO-dependent LTD induced by pharmacological activation of group I metabotropic glutamate receptors underwent significant reduction with aging and could be restored by inhibition of cGMP hydrolysis indicating that its age-related deficit is caused by an altered NO-cGMP signaling cascade.It is suggested that age-related alterations in corticostriatal synaptic plasticity may result from functional alterations in receptor-activated signaling cascades associated with increasing neuroinflammation and a prooxidant state.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurophysiology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.

ABSTRACT
Age-related alterations in the expression of genes and corticostriatal synaptic plasticity were studied in the dorsal striatum of mice of four age groups from young (2-3 months old) to old (18-24 months of age) animals. A significant decrease in transcripts encoding neuronal nitric oxide (NO) synthase and receptors involved in its activation (NR1 subunit of the glutamate NMDA receptor and D1 dopamine receptor) was found in the striatum of old mice using gene array and real-time RT-PCR analysis. The old striatum showed also a significantly higher number of GFAP-expressing astrocytes and an increased expression of astroglial, inflammatory, and oxidative stress markers. Field potential recordings from striatal slices revealed age-related alterations in the magnitude and dynamics of electrically induced long-term depression (LTD) and significant enhancement of electrically induced long-term potentiation in the middle-aged striatum (6-7 and 12-13 months of age). Corticostriatal NO-dependent LTD induced by pharmacological activation of group I metabotropic glutamate receptors underwent significant reduction with aging and could be restored by inhibition of cGMP hydrolysis indicating that its age-related deficit is caused by an altered NO-cGMP signaling cascade. It is suggested that age-related alterations in corticostriatal synaptic plasticity may result from functional alterations in receptor-activated signaling cascades associated with increasing neuroinflammation and a prooxidant state.

Show MeSH
Related in: MedlinePlus