Recent immunoelectron microscopic studies have revealed a low frequenc
y of synaptic membrane differentiations on ACh (ChAT-immunostained) ax
on terminals (boutons or varicosities) in adult rat cerebral cortex, h
ippocampus and neostriatum, suggesting that, besides synaptic transmis
sion, diffuse transmission by ACh prevails in many regions of the CNS.
Cytological analysis of the immediate microenvironment of these ACh t
erminals, as well as currently available immunocytochemical data on th
e cellular and subcellular distribution of ACh receptors, is congruent
with this view. At least in brain regions densely innervated by ACh n
eurons, a further aspect of the diffuse transmission paradigm is envis
aged: the existence of an ambient level of ACh in the extracellular sp
ace, to which all tissue elements would be permanently exposed. Recent
experimental data on the various molecular forms of AChE and their pr
esumptive role at the neuromuscular junction support this hypothesis.
As in the peripheral nervous system, degradation of ACh by the prevale
nt G(4) form of AChE in the CNS would primarily serve to keep the extr
asynaptic, ambient level of ACh within physiological limits, rather th
an totally eliminate ACh from synaptic clefts. Long-lasting and widesp
read electrophysiological effects imputable to ACh in the CNS might be
explained in this manner. The notions of diffuse transmission and of
an ambient level of ACh in the CNS could also be of clinical relevance
, in accounting for the production and nature of certain cholinergic d
eficits and the efficacy of substitution therapies. (C) 1997 Elsevier
Science Ltd.