Genetically modified mice and their importance in psychopharmacology
Just as adding genes from a complex to a simpler organism (for example,
from man to a fruit fly) may be helpful in understanding the function of a
gene, so it may help to understand how a gene functions by eliminating it.
To date, most gene ‘‘knock-out’’ studies have been undertaken in mice
because of:
(a) the relative ease with which genes can be manipulated and eliminated;
(b) the relatively rapid rate at which mice breed;
(c) their well established and relatively complex behaviour.
The success, and also the limitations of the gene elimination strategy can be
illustrated by studies on the molecular basis of memory and learning. In the
early 1980s it had been shown that the glutamate NMDA receptor was an
essential component of memory formation, the term ‘‘long-term potentiation’’
(LTP) being applied to the molecular mechanism involved. The drugs
which were then available were limited in their specificity for the NMDA
receptor but by selectively deleting genes thought to be involved in memory
it was possible to identify the precise components of the NMDA-linked
messenger complex located in the hippocampus. Further studies enabled
genes ranging from those encoding neurotransmitter receptors, protein kinases and transcription factors to be identified. However, there are
limitations to these techniques which should be considered.
A major problem with ‘‘knock-out’’ technology relates to the need to
delete the gene at the very early stage of embryonic development. Often this
results in the death of the neonate. Even if the gene is not essential for
survival, it could have a key role to play in development that is unrelated to
neuronal plasticity. Thus the deficits in learning and memory seen in the
mature mouse could be the result of a developmental defect rather than a
specific abnormality in the NMDA receptor complex. Alternatively, the
deletion of a gene that from experimental studies might be expected to have
a major effect on learning and memory in practice may have no apparent
effect. This is due to the mechanism of compensation whereby other genes
take over the function of the deleted gene.
Thus developing ‘‘knock-out’’ mice to understand the function of a
particular gene gives little information on the timing when the gene
becomes active. Nor does it necessarily reflect the location of the gene in the
intact (wild-type) mouse or indeed, the long-term effect of the nervous
system on its function. Nevertheless, these are largely technical drawbacks
that will undoubtedly shortly be solved. In principle, studying the actions
of psychotropic drugs on genetically modified animals will allow the
detrimental effects of a deleted gene on the general health of the animal to
be avoided. Such an approach will also allow investigations of the
interactions between neuronal signalling pathways by assessing the
synergistic interactions between the behavioural and other biological effects
of the deleted gene and drugs.
Just as adding genes from a complex to a simpler organism (for example,
from man to a fruit fly) may be helpful in understanding the function of a
gene, so it may help to understand how a gene functions by eliminating it.
To date, most gene ‘‘knock-out’’ studies have been undertaken in mice
because of:
(a) the relative ease with which genes can be manipulated and eliminated;
(b) the relatively rapid rate at which mice breed;
(c) their well established and relatively complex behaviour.
The success, and also the limitations of the gene elimination strategy can be
illustrated by studies on the molecular basis of memory and learning. In the
early 1980s it had been shown that the glutamate NMDA receptor was an
essential component of memory formation, the term ‘‘long-term potentiation’’
(LTP) being applied to the molecular mechanism involved. The drugs
which were then available were limited in their specificity for the NMDA
receptor but by selectively deleting genes thought to be involved in memory
it was possible to identify the precise components of the NMDA-linked
messenger complex located in the hippocampus. Further studies enabled
genes ranging from those encoding neurotransmitter receptors, protein kinases and transcription factors to be identified. However, there are
limitations to these techniques which should be considered.
A major problem with ‘‘knock-out’’ technology relates to the need to
delete the gene at the very early stage of embryonic development. Often this
results in the death of the neonate. Even if the gene is not essential for
survival, it could have a key role to play in development that is unrelated to
neuronal plasticity. Thus the deficits in learning and memory seen in the
mature mouse could be the result of a developmental defect rather than a
specific abnormality in the NMDA receptor complex. Alternatively, the
deletion of a gene that from experimental studies might be expected to have
a major effect on learning and memory in practice may have no apparent
effect. This is due to the mechanism of compensation whereby other genes
take over the function of the deleted gene.
Thus developing ‘‘knock-out’’ mice to understand the function of a
particular gene gives little information on the timing when the gene
becomes active. Nor does it necessarily reflect the location of the gene in the
intact (wild-type) mouse or indeed, the long-term effect of the nervous
system on its function. Nevertheless, these are largely technical drawbacks
that will undoubtedly shortly be solved. In principle, studying the actions
of psychotropic drugs on genetically modified animals will allow the
detrimental effects of a deleted gene on the general health of the animal to
be avoided. Such an approach will also allow investigations of the
interactions between neuronal signalling pathways by assessing the
synergistic interactions between the behavioural and other biological effects
of the deleted gene and drugs.
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