Some individuals maintain high cognitive functioning at older ages. Here we show that mechanisms for long-term depression differ in aged rodents that maintain cognitive performance compared to young adults. Our results imply that cognitive abilities may be sustained in aged individuals by a switch in synaptic plasticity mechanisms.
Long-term depression (LTD) in sensory cortices depends on the activation of NMDA receptors. Here, we report that in visual cortical slices, the induction of LTD (but not long-term potentiation) also requires the activation of receptors coupled to the phospholipase C (PLC) pathway. Using immunolesions in combination with agonists and antagonists, we selectively manipulated the activation of ␣1 adrenergic, M1 muscarinic, and mGluR5 glutamatergic receptors. Inactivation of these PLC-coupled receptors prevents the induction of LTD, but only when the three receptors were inactivated together. LTD is fully restored by activating any one of them or by supplying intracellular D-myo-inositol-1,4,5-triphosphate (IP 3 ). LTD was also impaired by intracellular application of PLC or IP 3 receptor blockers, and it was absent in mice lacking PLC1, the predominant PLC isoform in the forebrain. We propose that visual cortical LTD requires a minimum of PLC activity that can be supplied independently by at least three neurotransmitter systems. This essential requirement places PLC-linked receptors in a unique position to control the induction of LTD and provides a mechanism for gating visual cortical plasticity via extra-retinal inputs in the intact organism.
We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.
A novel terpolymer of acrylamide (AM), 4-vinylpyridine (VP), and 2-acrylamide-2-methylpropanesulfonic acid (AMPS) was synthesized through free radical polymerization and characterized by proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, elemental analysis, and static light scattering measurement. The monomer ratio was shown to be the predominant factor to the fluid-loss control performance of this polymer in drilling fluids. The terpolymer under optimal polymerization conditions (PAAV) was prepared, and the dipolymer of AM and AMPS (PAA) was synthesized as a contrast sample. In an American Petroleum Institute (API) filtration test of bentonite-based mud with 10% CaCl 2 contamination after a 16 h aging at 150 °C, mud with 1% PAAV maintained an API filtrate volume (FL API ) of 4.8 mL, whereas mud with 1% PAA reached a FL API of 96.0 mL. The fluid-loss control mechanism of PAAV was investigated through adsorption experiments, ζ potential measurements, and particle size distribution analysis. The results illustrate that the introduction of VP units into a polymer molecule greatly improves the temperature resistance performance of the polymer and enhances the interaction between the polymer and bentonite, which improves colloidal properties of bentonite particles, and these make PAAV a pronounced fluidloss control agent in deep gypsum drilling operations.
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