Ethanol inhibits neuritogenesis induced by astrocyte muscarinic receptors

Abstract

In utero alcohol exposure can lead to fetal alcohol spectrum disorders, characterized by cognitive and behavioral deficits. In vivo and in vitro studies have shown that ethanol alters neuronal development. We have recently shown that stimulation of M3 muscarinic receptors in astrocytes increases the synthesis and release of fibronectin, laminin, and plasminogen activator inhibitor-1, causing neurite outgrowth in hippocampal neurons. As M3 muscarinic receptor signaling in astroglial cells is strongly inhibited by ethanol, we hypothesized that ethanol may also inhibit neuritogenesis in hippocampal neurons induced by carbachol-stimulated astrocytes. In the present study we report that the effect of carbachol-stimulated astrocytes on hippocampal neuron neurite outgrowth was inhibited in a concentration-dependent manner (25–100 mM) by ethanol. This effect was due to the inhibition of the release of fibronectin, laminin, and plasminogen activator inhibitor-1. Similar effects on neuritogenesis and on the release of astrocyte extracellular proteins were observed after the incubation of astrocytes with carbachol in the presence of 1-butanol, another short-chain alcohol that, like ethanol, is a competitive substrate for phospholipase D, but not by tert-butanol, its analogue that is not a substrate for this enzyme. This study identifies a potential novel mechanism involved in the developmental effects of ethanol mediated by the interaction of ethanol with cell signaling in astrocytes, leading to an impairment in neuron-astrocyte communication.

Ethanol impairs muscarinic receptor-induced neuritogenesis in rat hippocampal slices: Role of astrocytes and extracellular matrix proteins

“…1). These findings confirm those previously obtained in co-cultures of astrocytes and neurons [17, 23]. …”

“…As ethanol had been reported to inhibit the signaling pathways activated by M3 muscarinic receptors in astrocytes [22], it was hypothesized that it may also inhibit carbachol-stimulated, astrocyte-induced neuritogenesis in hippocampal neurons, by inhibiting the release of neuritogenic factors. Indeed, incubation of astrocytes with ethanol, at concentrations as low as 25 mM (corresponding to 0.115 mg/dl), in the presence of carbachol, followed by wash-out, inhibited the effects of carbachol on axonal length and on minor neurite length by inhibiting phospholipase D [23]. By the same mechanism, ethanol also inhibited carbachol-induced increases in fibronectin and laminin-1 in the astrocyte lysate and in the medium [23].…”

“…Indeed, incubation of astrocytes with ethanol, at concentrations as low as 25 mM (corresponding to 0.115 mg/dl), in the presence of carbachol, followed by wash-out, inhibited the effects of carbachol on axonal length and on minor neurite length by inhibiting phospholipase D [23]. By the same mechanism, ethanol also inhibited carbachol-induced increases in fibronectin and laminin-1 in the astrocyte lysate and in the medium [23]. We are not aware of any other study showing an effect of ethanol on fibronectin in the CNS, but one study showed that chronic ethanol exposure followed by ethanol withdrawal decreases the levels of laminin-1 in the hippocampus indicating that the extracellular matrix is indeed a target of ethanol in vivo [62].…”

Glia and Neurodevelopment: Focus on Fetal Alcohol Spectrum Disorders

“…We have characterized several mechanisms by which ethanol affects astrocyte secretion: Ethanol reduces the release of neuritogenic ECM proteins laminin and fibronectin stimulated by muscarinic receptors in astrocytes (35), which may be due to the perturbation of the secretory pathway induced by ethanol in astrocytes (118). …”

Manganese protects against the effects of alcohol on hypothalamic puberty-related hormones

“…The actions of all of these are dependent upon their specific receptor activation and the interactive participation of the neuronal circuits and glial cells responsible for their synthesis and secretion. Importantly, alcohol (ALC) suppresses prepubertal LHRH/LH secretion [10-14] and has also been shown to impair neuronal and glial cell developmental communications [15-16], as well as specific functions with regard to neuronal/glial interactions involved in LHRH release [17-22]. Defining methods to ameliorate the suppressive effects of ALC on prepubertal LHRH/LH secretion is of importance.…”