The muscarinic acetylcholine receptor (mAChR) has been considered one of the neurotransmitter receptors regulating hippocampal synaptic plasticity, which likely plays a critical role in learning and memory. In previous studies, however, muscarinic agonists were used at relatively high concentrations, and the subtype selectivity of muscarinic antagonists was not satisfactory. Thus, it remains to be answered whether physiological levels of ACh are involved in the regulation of synaptic plasticity and which mAChR subtypes are responsible for such effects. We found in this study that a low concentration (50 nM) of carbachol enhanced long-term potentiation (LTP) of excitatory synaptic transmission in mouse hippocampal slices. Notably, this enhancing effect was abolished in M 1 mAChR knock-out (KO) but not in M 3 mAChR KO mice, although LTP itself was intact in both mutant mice. Furthermore, we found that repetitive stimulation in the stratum oriens, which presumably triggered the release of endogenous ACh from cholinergic terminals, could enhance LTP in wild-type mice but not in M 1 mAChR KO mice. These results suggest that physiologically released ACh from cholinergic fibers modulates hippocampal synaptic plasticity through the postsynaptic M 1 mAChR activation.

Taken together, these results show that Dicer is essential during early retinal development.

In the retina, both neurons and glia differentiate from a common progenitor population. CD44 cell surface antigen is a hyaluronic acid receptor expressed on mature Mü ller glial cells. We found that in the developing mouse retina, expression of CD44 was transiently observed at or around birth in a subpopulation of c-kit-positive retinal progenitor cells. During in vitro culture, purified CD44/c-kit-positive retinal progenitor cells exclusively differentiated into Mü ller glial cells and not into neurons, suggesting that CD44 marks a subpopulation of retinal progenitor cells that are fated to become glia. Overexpression of CD44 inhibited the extension of processes by the neural retina (Rich et al. 1995), and protecting neurons from damage (Garcia and Vecino 2003). Furthermore, they act as neural progenitors to regenerate neurons in response to acute damage, especially in lower vertebrates (Dyer and Cepko 2000;Ooto et al. 2004;Karl et al. 2008;Osakada et al. 2008). As in the brain, Müller glial cells are thought to differentiate along with neurons from a common progenitor in the retina (Cepko 1993 (Furukawa et al. 1997;Hojo et al. 2000). However, known markers of glial cell lineages -brain glial markers included -seem to expressed relatively late in glial differentiation. Therefore, identification of early as well as cell surface markers would greatly facilitate the elucidation of mechanisms governing neuron-glia cell fate decisions. CD44 is a widely expressed transmembrane glycoprotein and cell surface receptor for hyaluronic acid (HA) (Ponta et al. 2003). It is thought to mediate cell migration, adhesion, tissue differentiation, and cancer metastasis. Through its relatively long intracellular domain, HA-CD44 interactions stimulate Rac1 signaling, leading to cytoskeletal effects and cell migration in astrocytes (Ponta et al. 2003). Roles for HA and CD44 have been suggested in neural systems. HA is one of the major glycosaminoglycans in the extracellular matrix and plays important roles in morphogenesis, remodeling, and integrity of the CNS. In the uninjured CNS, expression of CD44 is restricted to astrocytes in the white matter. In the retina in an injured or degenerating condition, expression of CD44 has been observed (Kuhrt et al. 1997;Chaitin and Brun-Zinkernage 1998). Localization of CD44 to Müller cell apical microvilli has been shown by immunostaining in normal mature rodent retina (Chaitin et al. 1994;Chaitin and Brun-Zinkernage 1998). However, its expression in developing retina has not been reported before. We found that CD44 was transiently expressed in developing mouse retina at around the P1 stage. CD44-labeled retinal cells were fated to differentiate into Müller glial cells, suggesting that CD44 labels the subset of retinal progenitor cells that becomes Müller glial cells. Experimental proceduresMice and reagents Enhanced green fluorescent protein (EGFP) transgenic mice, which express the EGFP gene ubiquitously via the Cytomegalovirus early enhancer element and chicken beta-actin promoter, w...