α-Synuclein Regulates Development and Function of Cholinergic Enteric Neurons in the Mouse Colon.

Alpha-Synuclein (α-Syn) is expressed in the central nervous system and the nervous system of the gut (enteric nervous system, ENS), and is well known to be the major constituent of Lewy bodies which are the hallmark of Parkinson's disease. Gastrointestinal disorders frequently manifest several years before motor deficits develop in Parkinson's patients. Despite extensive research on pathological rodent models, the physiological role of α-Syn in the normal ENS is unclear hampering analysis of its neuropathology. We compared the ENS in colons of α-Syn-knockout (α-Syn KO) and wild-type mice using immunohistochemistry and calcium-imaging of responses to synaptic input. We found that α-Syn is predominantly expressed in cholinergic varicosities, which contain vesicular acetylcholine transporter. α-Syn KO mice had higher enteric neuron density and a larger proportion of cholinergic neurons, notably those containing calretinin, demonstrating a role for α-Syn in regulating development of these neurons. Moreover, α-Syn deletion enhanced the amplitude of synaptically activated [Ca2+]i transients that are primarily mediated by acetylcholine activating nicotinic receptors suggesting that α-Syn modulates the availability of acetylcholine in enteric nerve terminals.

Enteric nervous system assembly: Functional integration within the developing gut.

Co-ordinated gastrointestinal function is the result of integrated communication between the enteric nervous system (ENS) and "effector" cells in the gastrointestinal tract. Unlike smooth muscle cells, interstitial cells, and the vast majority of cell types residing in the mucosa, enteric neurons and glia are not generated within the gut. Instead, they arise from neural crest cells that migrate into and colonise the developing gastrointestinal tract. Although they are "later" arrivals into the developing gut, enteric neural crest-derived cells (ENCCs) respond to many of the same secreted signalling molecules as the "resident" epithelial and mesenchymal cells, and several factors that control the development of smooth muscle cells, interstitial cells and epithelial cells also regulate ENCCs. Much progress has been made towards understanding the migration of ENCCs along the gastrointestinal tract and their differentiation into neurons and glia. However, our understanding of how enteric neurons begin to communicate with each other and extend their neurites out of the developing plexus layers to innervate the various cell types lining the concentric layers of the gastrointestinal tract is only beginning. It is critical for postpartum survival that the gastrointestinal tract and its enteric circuitry are sufficiently mature to cope with the influx of nutrients and their absorption that occurs shortly after birth. Subsequently, colonisation of the gut by immune cells and microbiota during postnatal development has an important impact that determines the ultimate outline of the intrinsic neural networks of the gut. In this review, we describe the integrated development of the ENS and its target cells.

Activation of neuronal SST1 and SST2 receptors decreases neurogenic secretion in the guinea-pig jejunum.

BACKGROUND: Vasoactive intestinal peptide (VIP) submucosal neurons, the main regulators of gut secretion, display inhibitory postsynaptic potentials mediated by somatostatin (SOM) acting on SST(1) and SST(2) receptors (SSTR(1), SSTR(2)) in the guinea-pig small intestine. We investigated the implications of this for neurally-evoked mucosal secretion. METHODS: Mucosal-submucosal preparations from guinea-pig jejunum were mounted in Ussing chambers to measure Cl(-) secretion, measured by short circuit current (I(sc)). All drugs were added serosally. Veratridine (1 µmol L(-1)) was used to stimulate neurons and provide a robust secretory response for pharmacological testing.5-hydroxytrptamine (5-HT, 300 nmol L(-1)) was used to specifically activate non-cholinergic secretomotor neurons, while 1,1-dimethyl-4-phenylpiperazinium (DMPP, 10 µmol L(-1)) was used to stimulate all secretomotor neurons. KEY RESULTS: Somatostatin (50 nmol L(-1)) induced a tetrodotoxin (TTX, 1 µmol L(-1))-sensitive decrease in secretion. Somatostatin also reduced the veratridine-induced increase in I(sc). The effects of SOM were significantly reduced by blocking SSTR(1) and SSTR(2) individually or together. Blocking SSTR(1) abolished the inhibition produced by SOM. Quantitative PCR demonstrated that SSTR(1) and SSTR(2) were much more highly expressed in the submucosa than the mucosa. Submucosal SSTR(1) expression was several fold higher than SSTR(2). Responses to DMPP (biphasic) and 5-HT (monophasic) were TTX-sensitive. Somatostatin significantly reduced the 5-HT-induced increase in I(sc), and the second, more sustained phase evoked by DMPP. CONCLUSIONS & INFERENCES: These data suggest that SOM exerts its antisecretory effects by suppressing firing of VIP secretomotor neurons, rather than via a direct action on mucosal enterocytes.