A Biphasic and Brain-Region Selective Down-Regulation of Cyclic Adenosine Monophosphate Concentrations Supports Object Recognition in the Rat

Background: We aimed to further understand the relationship between cAMP concentration and mnesic performance. Methods and Findings: Rats were injected with milrinone (PDE3 inhibitor, 0.3 mg/kg, i.p.), rolipram (PDE4 inhibitor, 0.3 mg/ kg, i.p.) and/or the selective 5-HT4R agonist RS 67333 (1 mg/kg, i.p.) before testing in the object recognition paradigm. Cyclic AMP concentrations were measured in brain structures linked to episodic-like memory (i.e. hippocampus, prefrontal and perirhinal cortices) before or after either the sample or the testing phase. Except in the hippocampus of rolipram treated-rats, all treatment increased cAMP levels in each brain sub-region studied before the sample phase. After the sample phase, cAMP levels were significantly increased in hippocampus (1.8 fold), prefrontal (1.3 fold) and perirhinal (1.3 fold) cortices from controls rat while decreased in prefrontal cortex (,0.83 to 0.62 fold) from drug-treated rats (except for milrinone+RS 67333 treatment). After the testing phase, cAMP concentrations were still increased in both the hippocampus (2.76 fold) and the perirhinal cortex (2.1 fold) from controls animals. Minor increase were reported in hippocampus and perirhinal cortex from both rolipram (respectively, 1.44 fold and 1.70 fold) and milrinone (respectively 1.46 fold and 1.56 fold)-treated rat. Following the paradigm, cAMP levels were significantly lower in the hippocampus, prefrontal and perirhinal cortices from drug-treated rat when compared to controls animals, however, only drug-treated rats spent longer time exploring the novel object during the testing phase (inter-phase interval of 4 h)

Carbachol-Induced Long-Term Synaptic Depression Is Enhanced During Senescence at Hippocampal CA3–CA1 Synapses

Dysregulation of the cholinergic transmitter system is a hallmark of Alzheimer's disease and contributes to an age-associated decline in memory performance. The current study examined the influence of carbachol, a cholinergic receptor agonist, on synaptic transmission over the course of aging. Extracellular excitatory postsynaptic field potentials were recorded from CA3–CA1 synapses in acute hippocampal slices obtained from young adult (5–8 mo) and aged (22–24 mo) male Fischer 344 rats. Bath application of carbachol elicited a transient depression of synaptic transmission, which was followed by a long-lasting depression (CCh-LTD) observed 90 min after carbachol cessation in both age groups. However, the magnitude of CCh-LTD was significantly larger in senescent animals and was attenuated by N-methyl-d-aspartate receptor blockade in aged animals. Blockade of L-type Ca2+ channels inhibited CCh-LTD to a greater extent in aged animals compared to young adults. Finally, the expression of CCh-LTD was dependent on protein synthesis. The results indicate that altered Ca2+ homeostasis or muscarinic activation of Ca2+ signaling contribute to the enhanced CCh-LTD during senescence

Rat schwann cells express M1-M4 muscarinic receptors subtypes

The expression of different muscarinic receptor subtypes was analyzed in immature Schwann cells obtained from sciatic nerve of 2-day neonatal rats. By using RT-PCR analysis, we demonstrated the presence of M1, M2, M3, and M4 receptor subtypes in cultured Schwann cells, with M2 displaying the highest expression levels. Muscarinic subtypes were also quantified by immunoprecipitation and [3H]QNB binding. With this approach, we found the levels of receptor expression to be M2 > M3 > M1. M4 is expressed at very low levels, and M5 receptor was not detectable. Moreover, we also demonstrated that stimulation of the receptors by muscarinic agonists activates previously described signal transduction pathways, leading to a decrease of cAMP and an increase of IP3 levels not associated with an efficient intracellular Ca2+ release. The presence and activity of particular muscarinic receptors in immature Schwann cells suggest that ACh may play an important role in Schwann cell development