Introduction 
gene. Second, the similarities in the predicted 
amino acid sequences suggested that the subunits 
are probably arranged to form a central pore or 
channel between them. Third, the presence in 
each subunit of four hydrophobic regions, each 
about 20 amino acids long, immediately sug- 
gested the probable disposition of the subunits, 
with four transmembrane domains (Ml, M2, M3, 
and M4) and intervening intra- and extracellular 
linking segments. More recent work has identi- 
fied a fifth subunit type € and has established the 
precise location of the acetylcholine-binding site 
and the existence of a family of nicotinic AChRs 
in the central nervous system; much has also been 
learned about the regulation of the receptor dur- 
ing muscle development and after denervation, 
and about the process of receptor desensitization. 
The nicotinic AChR belongs to a large class of 
neurotransmitter receptors that operate by selec- 
tively opening ion channels. Another, somewhat 
larger class of receptors acts through second mes- 
sengers. For example, the adrenergic receptors, 
which are responsible for controlling a number 
of vital functions such as heart rate and blood 
pressure, act through the intermediary of a class 
of so-called G proteins to activate the enzyme 
adenylate cyclase and increase the intracellular 
level of the important second messenger, cAMP. 
The second messenger, in turn, usually acts by 
stimulating protein kinases that modify (by add- 
ing phosphate groups) other proteins, including 
ion channels and proteins that regulate gene ex- 
pression in the responding cell. 
The regulation of gene expression by synapti- 
cally mediated second messenger systems has be- 
come one of the most active areas for research in 
molecular neuroscience. Whereas neurotransmit- 
ters usually result in changes that have a time 
course measured in the millisecond to second 
range, many of the most intriguing phenomena in 
neuroscience are those that occur over periods of 
hours, days, and even months or years. Recent 
work has demonstrated that in addition to their 
more or less immediate and short-lasting effects, 
under appropriate conditions (such as those we 
commonly associate with learning and memory) 
neurotransmitters may, through second messen- 
gers, activate a number of transcriptional regula- 
tory proteins that "turn on" various classes of 
genes. These, in turn, may regulate the expres- 
sion of yet other genes and thus unleash a com- 
plex cascade of events within the responding 
nerve cell, modifying its growth and altering its 
responsiveness to later neurotransmitter activa- 
tion over long periods of time. 
One of the major beneficiaries of the applica- 
tion of the new genetics to the nervous system has 
been the field of developmental neuroscience. 
Indeed it is no exaggeration to say that since the 
late 1970s this field has been transformed from 
an essentially descriptive science into one in 
which, for the first time, mechanistic explana- 
tions are emerging to account for the growTih of 
nerve cells and their processes, for the deploy- 
ment of cells into peripheral ganglia and within 
cortical layers or nuclear groups in the central 
nervous system, for the formation of specific pat- 
terns of connections, and for the elimination of 
redundant cells and inappropriate connections. 
Because of the complexity and inaccessibility 
of the mammalian central nervous system, until 
recently much of the most definitive work on 
neural development has been carried out in 
simpler forms such as the nematode C. elegans 
and the fruit fly Drosophila. It is difficult to sum- 
marize the broad sweep of this work, except to 
say that it has served to clarify the genetic mecha- 
nisms that determine the distinct front-to-back 
and top-to-bottom organization of all developing 
organisms, that determine not only which cells 
will become neurons but also how many neurons 
will be generated and what type they will be 
(e.g., sensory cells, interneurons, or motor 
cells), and that determine finally whether the 
neurons that are initially formed will survive. In 
some instances it is clear that the character or 
phenotype of the nerve cells is determined by 
their lineage; in other cases cell-cell interactions 
are more important, and the nature of the signals 
that developing cells transmit to their neighbors 
is currently being elucidated. Of special impor- 
tance are the molecules on the surfaces of cells 
that enable them to recognize and aggregate with 
other cells of like kind or enable them to migrate 
along other cells or across territories filled with 
extracellular matrix materials. While much re- 
mains to be discovered, the first fruits of this har- 
vest hold great promise for future progress in this 
important field. 
Finally, no account of progress in molecular 
neuroscience would be complete without refer- 
ence to the striking developments in our under- 
standing of the basis of some of the major genetic 
disorders that affect the nervous and related mus- 
cular systems. Perhaps the most striking of these 
developments has been the cloning of the gene 
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