The function of the glutamate–nitric oxide–cGMP pathway in brain in vivo and learning ability decrease in parallel in mature compared with young rats

Abstract

Aging is associated with cognitive impairment, but the underlying mechanisms remain unclear. We have recently reported that the ability of rats to learn a Y-maze conditional discrimination task depends on the function of the glutamate-nitric oxide-cGMP pathway in brain. The aims of the present work were to assess whether the ability of rats to learn this task decreases with age and whether this reduction is associated with a decreased function of the glutamate-nitric oxide-cGMP pathway in brain in vivo, as analyzed by microdialysis in freely moving rats. We show that 7-mo-old rats need significantly more (192 ± 64%) trials than do 3-mo-old rats to learn the Y-maze task. Moreover, the function of the glutamate-nitric oxide-cGMP pathway is reduced by 60 ± 23% in 7-mo-old rats compared with 3-mo-old rats. The results reported support the idea that the reduction in the ability to learn the Y-maze task (and likely other types of learning) of mature compared with young rats would be a consequence of reduced function of the glutamate-nitric oxide-cGMP pathway.Aging is associated with cognitive impairment, but the underlying mechanisms remain unclear. The molecular bases for different types of learning are not well known. NMDA receptors play a crucial role in some types of learning. Activation of NMDA receptors leads to increased calcium in the post-synaptic neuron. Calcium binds to calmodulin and activates neuronal nitric oxide synthase (nNOS) in those neurons, which express both the NMDA receptors and this enzyme, increasing nitric oxide (NO). NO, in turn, activates soluble guanylate cyclase, increasing cGMP. Part of this cGMP is released to the extracellular fluid through cGMP transporters present in the cell membrane (Sager 2004).Several reports indicate that activation of this glutamate-NO-cGMP pathway is involved in some forms of learning (Danysz et al. 1995;Chen et al. 1997;Meyer et al. 1998). NO seems to mediate at least part of the role of NMDA receptors in learning. This is supported by studies showing that inhibition of NO synthase reduces learning of some spatial tasks (Ingram et al. 1998a,b;Zou et al. 1998) The role of NO in learning may be mediated by its activation of soluble guanylate cyclase and the increase in cGMP. Some reports indicate that soluble guanylate cyclase and cGMP are important in learning and memory. Bernabeu et al. (1996Bernabeu et al. ( , 1997 showed that, in rats, passive avoidance learning was associated with a time-dependent, learning-specific increase in cGMP (Bernabeu et al. 1996) and in cGMP-dependent protein kinase activity in hippocampus (Bernabeu et al. 1997) The same group also showed that administration of a membrane permeable analog of cGMP facilitated memory consolidation (Bernabeu et al. 1996), while bilateral intrahippocampal administration of an inhibitor of soluble guanylate cyclase caused full amnesia for inhibitory avoidance learning when given immediately after training (Bernabeu et al. 1997). These data indicate that the increase in cGMP produced by guanylate cycla...

Effects of YC-1 on Learning and Memory Functions of Aged Rats

“…The neural system underlying emotional memory involves the amygdala [21]. Consistently, in a previous behavioral study, it was shown that aged rats required significantly more trials than young rats to learn the maze task [22]. Aged rats’ memory functions are generally impaired on a wide variety of navigation tasks (e.g., Morris water maze task, T-maze, and Barnes circular platform corridor mazes) [23].…”

Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats

“…26 Reduced function of the pathway in cerebellum is associated with reduced learning of the Y-maze in many pathological situations in rats: developmental exposure to methylmercury or polychlorinated biphenyls, 27,28 rats with chronic hyperammonemia 13 or with minimal hepatic encephalopathy (MHE) due to portacaval shunt 14 or bile duct ligation 29 or in aging of the rats. 30 Also, developmental exposure to PBDE99 enhances the function of the pathway and learning ability. 31 Moreover, in rats with hyperammonemia or MHE, restoring the function of the pathway also restores learning ability.…”

Cyclic GMP and Nitric Oxide Synthase in Aging and Alzheimer's Disease

“…Since activation of NMDA receptors leads to an increase of calcium in the post-synaptic neurons, several reports have implicated the role of the glutamate/NO/cGMP pathway in learning and memory [18,37,42]. There is further indication that learning and memory impairment in older animals is a consequence of reduced function of the glutamate/NO/cGMP pathway in the aged brain [47] and probably also alteration in the cholinergic signaling. The increase in PDE expression and activity may lead to more intensive cGMP hydrolysis in the senescent brain.…”