Age‐related Changes in the NMDA Receptor/Nitric Oxide/cGMP Pathway in the Hippocampus and Cerebellum of Freely Moving Rats Subjected to Transcerebral Microdialysis

Abstract

The N-methyl-D-aspartate (NMDA) receptor/nitric oxide synthase/guanylate cyclase pathway was studied during aging by monitoring extracellular cGMP in the rat hippocampus and cerebellum during in vivo microdialysis. In the hippocampus the basal cGMP efflux decreased by 50% from 3 to 12 months of age, whereas it remained constant with age in the cerebellum. Locally perfused NMDA (1 mM) evoked remarkable cGMP responses in 3-month-old rats; in the hippocampus the cGMP production was already dramatically reduced at 12 months, whereas in the cerebellum a similar impairment occurred much later (24 months). The nitric oxide donor S-nitroso-N-penicillamine (1 mM) elicited cGMP responses which slightly decreased from 3 to 12-24 months in the hippocampus, while no significant decrement with age could be seen in the cerebellum. Local perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 1 mM) produced large increases in hippocampal cGMP levels. The response decreased at 12 and 24 months, apparently in parallel with the fall in the basal level of cGMP. No significant differences across ages were observed following IBMX infusion in the cerebellum. The decreases in basal outflow and in the NMDA-evoked cGMP response seen in the aged hippocampus were not compensated for by supplying L-arginine. Infusion of D-serine (1 mM) enhanced (150-200%) extracellular cGMP in the cerebellum with no age-related differences. The activity in vitro of hippocampal nitric oxide synthase at 24 months was 33% lower than at 3 months, whereas the cerebellar enzyme did not show any age-related decay.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of Rat cGMP‐Binding cGMP‐Specific Phosphodiesterase mRNA in Purkinje Cell Layers During Postnatal Neuronal Development

“…Levels of cGMP in the hippocampus and cerebellum were indicated to decrease during aging [57]. Soluble pl guanylate cyclase, which was detected at a low level in the brain of the mouse embryo, was widely observed in the adult brain including Purkinje cell layers of the cerebellum.…”

Phosphodiesterase 9A Regulates Central cGMP and Modulates Responses to Cholinergic and Monoaminergic Perturbation In Vivo

“…Consistent with the hypothesis that elevation of cGMP enhances hippocampal plasticity, learning, and memory, pharmacological studies of inhibitors of cGMP hydrolysis, including PDE9A inhibitors, have found that these compounds enhanced longterm potentiation (LTP) and performance in novel object recognition tasks in a time-sensitive fashion and in deficit settings that include tryptophan depletion and aging (Prickaerts et al, 2002a(Prickaerts et al, ,b, 2004Boess et al, 2004;Rutten et al, 2007;Menniti et al, 2008;van Donkelaar et al, 2008;van der Staay et al, 2008;Hutson et al, 2011). Age-related deficits in the N-methyl-D-aspartic acid (NMDA)/nitric oxide (NO)/cGMP pathway (Vallebuona and Raiteri, 1995;Chalimoniuk and Strosznajder, 1998) may explain the beneficial effects of cGMP modulation on cognitive impairment during normal aging.…”

“…Therapeutic modulation of cGMP has been proposed as a clinical approach to memory deficits (Prickaerts et al, 2002aBoess et al, 2004;Puzzo et al, 2005Puzzo et al, , 2006Puzzo et al, , 2008Puzzo et al, , 2009de Vente et al, 2006;van der Staay et al, 2008). Early studies used nonselective cGMP PDE inhibitors such as zaprinast, later progressing to selective PDE5 inhibitors such as sildenafil (Puzzo et al, 2008(Puzzo et al, , 2009) and PDE9A inhibitors such as BAY 73-6991 to demonstrate improvements in rodent learning and memory models as well as enhanced LTP in hippocampal slices from aged animals (van der Staay et al, 2008).…”

Brain nitric oxide: Regional characterisation of a real-time microelectrochemical sensor

“…A high density of NMDA receptors has been confirmed in the prefrontal cortex (Monaghan and Cotman, 1985) and it is postulated that NO exerts strong influence on glutamatergic neurotransmission by directly interacting with the receptor (Bernstein et al, 2005). Various other reports have indicated that NOS activity was decreased in the hippocampus of aged rats but not in the cortex or cerebellum (Mollace et al, 1995;Vallebuona and Raiteri, 1995), however, alternative investigators reported increased activity in both the hippocampus and cerebellum of aged rats (Chalimoniuk and Strosznajder, 1998). These findings have all been quantified by indirect methods which is a major disadvantage of the vast majority of existing analytical techniques.…”