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Alzheimer transgenic mouse models come of age
L. Olson – GDNF in rat Parkinson model
3 Unsicker, K. (1996) Cell Tissue Res. 286, 175–178 4 Kotzbauer, P. et al. (1996) Nature 384, 467–470 5 Durbec, P. et al. (1996) Nature 381, 789–793 6 Trupp, M. et al. (1996) Nature 381, 785–789 7 Jing, S. et al. (1996) Cell 85, 1113–1124 8 Treanor, J. et al. (1996) Nature 382, 80–83 9 Tomac, A. et al. (1995) Nature 373,
335–339 10 Henderson, C. et al. (1994) Science 266, 1062–1064 11 Buj-Bello, A. et al. (1995) Neuron 15, 821–828 12 Ebendal, T. et al. (1995) J. Neurosci. Res. 40, 276–284 13 Olson, L. (1996) Nat. Med. 2, 400–401 14 Olson, L. et al. (1991) Arch. Neurol. 48, 373–381 15 Sydow, O. et al. (1995) J. Neurol. 2, 1–10
RESEARCH
NEWS
16 Olson, L. (1993) Exp. Neurol. 124, 515 17 Friden, P. et al. (1993) Science 259, 373–377 18 Choi-Lundberg, D. et al. (1997) Science 275, 838–841 19 Sauer, H. and Oertel, W. (1994) Neuroscience 59, 401–415 20 Wood, M. et al. (1996) Trends Neurosci. 19, 497–501 21 Winkler, J. et al. (1997) Ann. Neurol. 41, 82–93 22 Nosrat, C. et al. Exp. Brain Res. (in press)
Alzheimer transgenic mouse models come of age It has been 90 years since Alois Alzheimer first described a patient with a form of dementia that later became known as Alzheimer’s disease (AD). In those 90 years, we have come a long way in our understanding of AD but the basic question, what causes Alzheimer’s dementia? is still not answered in the majority of cases of Alzheimer’s disease. Regardless of whether you believe that AD is caused by mismetabolism of the amyloid precursor protein (APP), by abnormal tau phosphorylation or by some other unknown mechanism, genetics has given us two handles on the disease. Firstly, mutations in APP, presenilin-1 (PS-1) and presenilin-2 (PS-2) cause Alzheimer’s disease, and secondly, inheritance of the ApoE4 allele is a strong risk factor for AD in most populations. Although known genetic mutations only account for a small proportion of cases of Alzheimer’s disease, a wealth of data has been generated about the proteins they affect and their possible involvement in the development of the disease.
Transgenic models with amyloid deposits In the latter part of 1996, several papers added to our knowledge of how mutations in APP and the presenilins might induce Alzheimer’s disease. One of these papers was the description of an APP overexpressing transgenic mouse created by Karen Hsiao at the University of Minnesota and her colleagues1. The transgene used the promoter and regulatory regions from the prion (PrP) gene to drive expression of the open reading frame for APP 695 containing the Swedish mutation (K670M:N671L). The Hsiao mouse differed from the APP mouse generated by Exemplar/Athena (the PDAPP mouse)2 in the choice of promoter (PDGF vs PrP in the Hsiao model), in the cDNA expressed (695/751/770 generated through alternate splicing of an APP minigene vs APP 695 used by Hsiao et al.), in the mutations used (V717F vs Swedish) and in the strain of mice used (outbred Swiss Webster 3 B6D2F1 vs SJL 3 C57Blk6).
The Hsiao mouse demonstrated amyloid deposits in the hippocampus and cortex that stained with thioflavin S and congo red (suggesting b sheet conformation) and were positive for Ab1-40 and Ab1-42 immunoreactivity at 12 months of age. Surrounding glia demonstrated GFAP immunoreactivity indicating an inflammatory response to the deposits. Immunoreactivity to complement pathway proteins and AD associated proteins was not reported, but staining for paired helical filaments and/or abnormal tau was negative at this age. The amyloid deposits were essentially identical to those seen in the PDAPP mouse, although the Athena mouse appears to develop deposits at an earlier age (6–9 months) which might reflect strain differences (some strains might deal with APP/Ab better than others), construct design (especially the contribution of the KPI containing transcripts absent from the Hsiao mouse) or overall levels of transgene derived Ab. What does seem likely however is that these two mice achieved a threshold level of Ab that is required for deposition to occur in the mouse brain, which was not achieved in other, non-depositing APP transgenic mice. In the Hsiao model, this level appears to be between 14 and 50 pm/g wet weight tissue (C. Eckman, pers. commun.). Both models showed an age dependent correlation between the elevation of Ab and the formation of deposits1,3. In the Hsiao mouse, Ab1-40 increased 5-fold and Ab1-42(43) increased 14-fold between the youngest age group (6–8 months) and the older age group (11–13 months)1. In the PDAPP mouse, total Ab levels increased 17-fold between the ages of 4 and 8 months and 500-fold between the ages of 4 and 18 months with the vast majority of the Ab being the Ab1-42(43) form3. Interestingly, deposits did not develop in regions of the brain usually spared in AD (the cerebellum) which mimics the ‘selective vulnerability’ seen in human AD brain regions. One major finding reported for the Hsiao aged transgenic animals was a deficit in learning and memory retention as tested by
Copyright © 1997, Elsevier Science Ltd. All rights reserved. 0166 - 2236/97/$17.00
escape latency in a modified Morris water maze and by spontaneous alternation in a Y maze1. Although the data is confounded by experimental variability and small changes, the older transgenic mice do show a significant difference in cognitive ability relative to non-transgenic littermates when compared to younger animals. Although these data are suggestive, more behavioral testing must be carried out on these mice before the extent of the deficit is fully elucidated. The creation of a mutant APP mouse showing elevated Ab, amyloid deposits and cognitive deficits suggests that APP mismetabolism is at the root of Alzheimer’s disease, at least in the case of AD caused by APP mutations. Some features of the disease however, most noticeably the formation of tau containing PHFs, activation of the full complement pathway and large scale neuronal loss, have yet to be reported. Work in progress on the PDAPP mouse has shown that some of the complement proteins are associated with a subset of plaques and that some dystrophic neurites associated with deposits are immunoreactive for phosphorylated tau (D. Games, pers. commun.). In addition, Bernd Sommer from Sandoz pharmaceuticals described a new thy-I directed APP751 (Swedish) mouse at the recent Neuroscience conference4 that forms deposits and shows immunoreactivity to phosphorylated tau protein both in dystrophic neurites and cell bodies. It is possible that these features may also be seen in older mice from the Hsiao line.
Presenilin transgenic mice The argument that the primary pathogenic lesion in AD is related to Ab rather than to tau was strengthened recently following reports of the effect of AD associated PS-1 mutations on APP processing. The first report5 demonstrated that the level of Ab1-42(43) relative to Ab1-40 was elevated in fibroblasts isolated from AD patients with a PS-1 mutation. This report was confirmed and extended by the observation that transgenic mice overexpressing mutant or wild
PII: S0166-2236(97)01093-X
TINS Vol. 20, No. 7, 1997
Karen Duff Mayo Clinic, Birdsall Building, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.
279
RESEARCH
NEWS
K. Duff – Transgenic models of Alzheimer’s disease
type human PS-1 cDNA under the control of the PDGF promoter showed an elevation in Ab1-42(43) but not Ab1-40 in the brains of mutant mice only6. This report has since been confirmed in other transgenic mice7,8 and in transfected cells9. Amyloid deposits have not been seen in PS-1 mutant mice at 8 months of age (P. Hyslop, pers. commun.) but this is not unexpected as it is thought that the level of Ab1-42(43), though elevated relative to the level in WT or nontransgenic mice, will not reach the levels that seem to be required for deposition in mice. There are, as yet, no reports of behavioral abnormalities and the mice appear healthy at over a year old.
What causes dementia? One important question that may be answerable through close examination of the Hsiao mice is the temporal relationship between the onset of behavioral problems (that presumably reflect hippocampal and cortical dysfunction) and the formation of amyloid deposits. If behavioral abnormalities precede deposit formation, then it suggests that either soluble or, more likely, partially fibrillar Ab is the cytotoxic entity that is responsible for cognitive impairment, and the deposition of amyloid into plaques might be a pathogenically unrelated consequence of high concentrations of Ab or, indeed, might be a protective cellular mechanism that clears the brain of toxic fibrils. PS mutant mice might also show behavioral deficits in the absence of amyloid deposits if low levels of soluble or partially fibrillar Ab1-42(43) are responsible. These observations would, of course, have crucial implications for drug design as plaque-busting drugs might prove to be ineffective if deposits are not pathogenic or, more worrying, might actually be detrimental, if deposits lock away harmful secreted Ab from the brain. The involvement of Ab but not plaques
in AD pathogenesis might also explain the apparent lack of correlation between plaque burden and degree of dementia in humans, and would help explain the finding by Hsiao et al.10 that transgenic FVB mice overexpressing mutant APP show behavioral deficits in the absence of deposits. Again, careful correlation between the level of Ab, the appearance of deposits and the onset of cognitive impairment may help to answer these questions. An alternative explanation, however, is that something other than Ab is the primary cause of AD dementia. The question ‘can we see AD related changes in the absence of APP?’ might be answered by examining a cross between a mutant PS mouse and an APP null. The intriguing finding that Ab1-42(43) is specifically elevated in cases of AD caused by APP mutations, PS-1 mutations and PS-2 mutations9 strongly suggests, however, that this form of Ab is somehow linked to the disease. A cross between the Hsiao APP mice and mutant PS-1 mice shows that the transgenes are additive in their effects on Ab1-42(43) (K. Duff, unpublished data). It will be interesting to see whether this increase is associated with a reduction in the age at which deposits form and a concomitant advance in cognitive impairment. Subtle differences between APP-associated AD and PS-1associated AD might also be picked up in a cross between the PDAPP mouse and the mutant PS-1 mouse described in Ref. 6 which are identical in terms of mouse strain and promoter choice. For example, the cerebellar plaques often seen in families with PS-1 mutations may appear in the doubly transgenic cross, but remain absent from the APP alone transgenic mouse. Another question that might be answered in examining PS-1 mutant mice alongside APP mutant mice is whether overexpression of APP itself might obscure parts of the
phenotype. One suggestion for the lack of neuronal loss in the APP overexpression mice is that increasing APP in general also leads to increased levels of the potentially neurotrophic APPs fragment and this might prevent cell death11. Although the PS-1 mice might not show amyloid deposits it is possible that they will show cell loss if the increase in Ab42(43) leads to a concomitant decrease in APPs. Although it would be premature to predict that the specific elevation of Ab1-42(43) relative to other forms of Ab peptide is the pathogenic mechanism in Alzheimer’s disease, it does seem remarkable that mutations in two unrelated genes affect the same pathway. The observation that elevation is also linked to amyloid deposition in the APP mice, and appears to be temporally linked to cognitive impairment, suggests that Ab1-42(43) may be at the root of these features of the disease. The exact sequence of events is still unclear but the transgenic models generated so far have already shown their utility in the dissection of this complex part of the pathology. References 1 Hsiao, K. et al. (1996) Science 274, 99–102 2 Games, D. et al. (1995) Nature 373, 523–527 3 Johnson-Wood, K. et al. Proc. Natl. Acad. Sci. U. S. A. (in press) 4 Sommer, B. et al. (1996) Soc. Neurosci. Abs. Vol. 22, p. 25 5 Scheuner, D. et al. (1996) Nat. Med. 2, 864–870 6 Duff, K. et al. (1996) Nature 383, 710–713 7 Borchelt, D. et al. (1996) Neuron 17, 1005–1013 8 Citron, M. et al. (1997) Nat. Med. 3, 67–72 9 Thinakaran, G. et al. (1996) Neuron 17, 181–190 10 Hsiao, K. et al. (1995) Neuron 15, 1203–1217 11 Yankner, B. (1996) Neuron 16, 921–932
TINS Editorial Policy Trends in Neurosciences is the leading neuroscience review journal (Impact Factor 19.972; SCI Journals Citation Reports® 1995), publishing timely and wide-ranging feature articles that enable neuroscientists to keep up to date in and around their own research fields. Reviews form the foundations of each issue and offer concise and authoritative summaries of important areas of neuroscientific research; Meeting Reports and Research News articles describe recent developments within a particular field; Perspectives discuss areas of historical, social and more oblique interest – offering interesting insights into current research as it applies to neuroscience; Viewpoints include more controversial or synthetic ideas. The Debate section provides a series of alternative viewpoints on a currently hotly debated topic. Perspectives on Disease discuss how basic neurobiological studies can be applied to neurological disease; Techniques offers readers a guide to new methods and their use. TINS articles are specially commissioned by the Editor, in consultation with the Advisory Editorial Board. All submissions are subject to peer and editorial review – commissioning does not guarantee publication.
280
TINS Vol. 20, No. 7, 1997
3 Unsicker, K. (1996) Cell Tissue Res. 286, 175–178 4 Kotzbauer, P. et al. (1996) Nature 384, 467–470 5 Durbec, P. et al. (1996) Nature 381, 789–793 6 Trupp, M. et al. (1996) Nature 381, 785–789 7 Jing, S. et al. (1996) Cell 85, 1113–1124 8 Treanor, J. et al. (1996) Nature 382, 80–83 9 Tomac, A. et al. (1995) Nature 373,
335–339 10 Henderson, C. et al. (1994) Science 266, 1062–1064 11 Buj-Bello, A. et al. (1995) Neuron 15, 821–828 12 Ebendal, T. et al. (1995) J. Neurosci. Res. 40, 276–284 13 Olson, L. (1996) Nat. Med. 2, 400–401 14 Olson, L. et al. (1991) Arch. Neurol. 48, 373–381 15 Sydow, O. et al. (1995) J. Neurol. 2, 1–10
RESEARCH
NEWS
16 Olson, L. (1993) Exp. Neurol. 124, 515 17 Friden, P. et al. (1993) Science 259, 373–377 18 Choi-Lundberg, D. et al. (1997) Science 275, 838–841 19 Sauer, H. and Oertel, W. (1994) Neuroscience 59, 401–415 20 Wood, M. et al. (1996) Trends Neurosci. 19, 497–501 21 Winkler, J. et al. (1997) Ann. Neurol. 41, 82–93 22 Nosrat, C. et al. Exp. Brain Res. (in press)
Alzheimer transgenic mouse models come of age It has been 90 years since Alois Alzheimer first described a patient with a form of dementia that later became known as Alzheimer’s disease (AD). In those 90 years, we have come a long way in our understanding of AD but the basic question, what causes Alzheimer’s dementia? is still not answered in the majority of cases of Alzheimer’s disease. Regardless of whether you believe that AD is caused by mismetabolism of the amyloid precursor protein (APP), by abnormal tau phosphorylation or by some other unknown mechanism, genetics has given us two handles on the disease. Firstly, mutations in APP, presenilin-1 (PS-1) and presenilin-2 (PS-2) cause Alzheimer’s disease, and secondly, inheritance of the ApoE4 allele is a strong risk factor for AD in most populations. Although known genetic mutations only account for a small proportion of cases of Alzheimer’s disease, a wealth of data has been generated about the proteins they affect and their possible involvement in the development of the disease.
Transgenic models with amyloid deposits In the latter part of 1996, several papers added to our knowledge of how mutations in APP and the presenilins might induce Alzheimer’s disease. One of these papers was the description of an APP overexpressing transgenic mouse created by Karen Hsiao at the University of Minnesota and her colleagues1. The transgene used the promoter and regulatory regions from the prion (PrP) gene to drive expression of the open reading frame for APP 695 containing the Swedish mutation (K670M:N671L). The Hsiao mouse differed from the APP mouse generated by Exemplar/Athena (the PDAPP mouse)2 in the choice of promoter (PDGF vs PrP in the Hsiao model), in the cDNA expressed (695/751/770 generated through alternate splicing of an APP minigene vs APP 695 used by Hsiao et al.), in the mutations used (V717F vs Swedish) and in the strain of mice used (outbred Swiss Webster 3 B6D2F1 vs SJL 3 C57Blk6).
The Hsiao mouse demonstrated amyloid deposits in the hippocampus and cortex that stained with thioflavin S and congo red (suggesting b sheet conformation) and were positive for Ab1-40 and Ab1-42 immunoreactivity at 12 months of age. Surrounding glia demonstrated GFAP immunoreactivity indicating an inflammatory response to the deposits. Immunoreactivity to complement pathway proteins and AD associated proteins was not reported, but staining for paired helical filaments and/or abnormal tau was negative at this age. The amyloid deposits were essentially identical to those seen in the PDAPP mouse, although the Athena mouse appears to develop deposits at an earlier age (6–9 months) which might reflect strain differences (some strains might deal with APP/Ab better than others), construct design (especially the contribution of the KPI containing transcripts absent from the Hsiao mouse) or overall levels of transgene derived Ab. What does seem likely however is that these two mice achieved a threshold level of Ab that is required for deposition to occur in the mouse brain, which was not achieved in other, non-depositing APP transgenic mice. In the Hsiao model, this level appears to be between 14 and 50 pm/g wet weight tissue (C. Eckman, pers. commun.). Both models showed an age dependent correlation between the elevation of Ab and the formation of deposits1,3. In the Hsiao mouse, Ab1-40 increased 5-fold and Ab1-42(43) increased 14-fold between the youngest age group (6–8 months) and the older age group (11–13 months)1. In the PDAPP mouse, total Ab levels increased 17-fold between the ages of 4 and 8 months and 500-fold between the ages of 4 and 18 months with the vast majority of the Ab being the Ab1-42(43) form3. Interestingly, deposits did not develop in regions of the brain usually spared in AD (the cerebellum) which mimics the ‘selective vulnerability’ seen in human AD brain regions. One major finding reported for the Hsiao aged transgenic animals was a deficit in learning and memory retention as tested by
Copyright © 1997, Elsevier Science Ltd. All rights reserved. 0166 - 2236/97/$17.00
escape latency in a modified Morris water maze and by spontaneous alternation in a Y maze1. Although the data is confounded by experimental variability and small changes, the older transgenic mice do show a significant difference in cognitive ability relative to non-transgenic littermates when compared to younger animals. Although these data are suggestive, more behavioral testing must be carried out on these mice before the extent of the deficit is fully elucidated. The creation of a mutant APP mouse showing elevated Ab, amyloid deposits and cognitive deficits suggests that APP mismetabolism is at the root of Alzheimer’s disease, at least in the case of AD caused by APP mutations. Some features of the disease however, most noticeably the formation of tau containing PHFs, activation of the full complement pathway and large scale neuronal loss, have yet to be reported. Work in progress on the PDAPP mouse has shown that some of the complement proteins are associated with a subset of plaques and that some dystrophic neurites associated with deposits are immunoreactive for phosphorylated tau (D. Games, pers. commun.). In addition, Bernd Sommer from Sandoz pharmaceuticals described a new thy-I directed APP751 (Swedish) mouse at the recent Neuroscience conference4 that forms deposits and shows immunoreactivity to phosphorylated tau protein both in dystrophic neurites and cell bodies. It is possible that these features may also be seen in older mice from the Hsiao line.
Presenilin transgenic mice The argument that the primary pathogenic lesion in AD is related to Ab rather than to tau was strengthened recently following reports of the effect of AD associated PS-1 mutations on APP processing. The first report5 demonstrated that the level of Ab1-42(43) relative to Ab1-40 was elevated in fibroblasts isolated from AD patients with a PS-1 mutation. This report was confirmed and extended by the observation that transgenic mice overexpressing mutant or wild
PII: S0166-2236(97)01093-X
TINS Vol. 20, No. 7, 1997
Karen Duff Mayo Clinic, Birdsall Building, 4500 San Pablo Rd, Jacksonville, FL 32224, USA.
279
RESEARCH
NEWS
K. Duff – Transgenic models of Alzheimer’s disease
type human PS-1 cDNA under the control of the PDGF promoter showed an elevation in Ab1-42(43) but not Ab1-40 in the brains of mutant mice only6. This report has since been confirmed in other transgenic mice7,8 and in transfected cells9. Amyloid deposits have not been seen in PS-1 mutant mice at 8 months of age (P. Hyslop, pers. commun.) but this is not unexpected as it is thought that the level of Ab1-42(43), though elevated relative to the level in WT or nontransgenic mice, will not reach the levels that seem to be required for deposition in mice. There are, as yet, no reports of behavioral abnormalities and the mice appear healthy at over a year old.
What causes dementia? One important question that may be answerable through close examination of the Hsiao mice is the temporal relationship between the onset of behavioral problems (that presumably reflect hippocampal and cortical dysfunction) and the formation of amyloid deposits. If behavioral abnormalities precede deposit formation, then it suggests that either soluble or, more likely, partially fibrillar Ab is the cytotoxic entity that is responsible for cognitive impairment, and the deposition of amyloid into plaques might be a pathogenically unrelated consequence of high concentrations of Ab or, indeed, might be a protective cellular mechanism that clears the brain of toxic fibrils. PS mutant mice might also show behavioral deficits in the absence of amyloid deposits if low levels of soluble or partially fibrillar Ab1-42(43) are responsible. These observations would, of course, have crucial implications for drug design as plaque-busting drugs might prove to be ineffective if deposits are not pathogenic or, more worrying, might actually be detrimental, if deposits lock away harmful secreted Ab from the brain. The involvement of Ab but not plaques
in AD pathogenesis might also explain the apparent lack of correlation between plaque burden and degree of dementia in humans, and would help explain the finding by Hsiao et al.10 that transgenic FVB mice overexpressing mutant APP show behavioral deficits in the absence of deposits. Again, careful correlation between the level of Ab, the appearance of deposits and the onset of cognitive impairment may help to answer these questions. An alternative explanation, however, is that something other than Ab is the primary cause of AD dementia. The question ‘can we see AD related changes in the absence of APP?’ might be answered by examining a cross between a mutant PS mouse and an APP null. The intriguing finding that Ab1-42(43) is specifically elevated in cases of AD caused by APP mutations, PS-1 mutations and PS-2 mutations9 strongly suggests, however, that this form of Ab is somehow linked to the disease. A cross between the Hsiao APP mice and mutant PS-1 mice shows that the transgenes are additive in their effects on Ab1-42(43) (K. Duff, unpublished data). It will be interesting to see whether this increase is associated with a reduction in the age at which deposits form and a concomitant advance in cognitive impairment. Subtle differences between APP-associated AD and PS-1associated AD might also be picked up in a cross between the PDAPP mouse and the mutant PS-1 mouse described in Ref. 6 which are identical in terms of mouse strain and promoter choice. For example, the cerebellar plaques often seen in families with PS-1 mutations may appear in the doubly transgenic cross, but remain absent from the APP alone transgenic mouse. Another question that might be answered in examining PS-1 mutant mice alongside APP mutant mice is whether overexpression of APP itself might obscure parts of the
phenotype. One suggestion for the lack of neuronal loss in the APP overexpression mice is that increasing APP in general also leads to increased levels of the potentially neurotrophic APPs fragment and this might prevent cell death11. Although the PS-1 mice might not show amyloid deposits it is possible that they will show cell loss if the increase in Ab42(43) leads to a concomitant decrease in APPs. Although it would be premature to predict that the specific elevation of Ab1-42(43) relative to other forms of Ab peptide is the pathogenic mechanism in Alzheimer’s disease, it does seem remarkable that mutations in two unrelated genes affect the same pathway. The observation that elevation is also linked to amyloid deposition in the APP mice, and appears to be temporally linked to cognitive impairment, suggests that Ab1-42(43) may be at the root of these features of the disease. The exact sequence of events is still unclear but the transgenic models generated so far have already shown their utility in the dissection of this complex part of the pathology. References 1 Hsiao, K. et al. (1996) Science 274, 99–102 2 Games, D. et al. (1995) Nature 373, 523–527 3 Johnson-Wood, K. et al. Proc. Natl. Acad. Sci. U. S. A. (in press) 4 Sommer, B. et al. (1996) Soc. Neurosci. Abs. Vol. 22, p. 25 5 Scheuner, D. et al. (1996) Nat. Med. 2, 864–870 6 Duff, K. et al. (1996) Nature 383, 710–713 7 Borchelt, D. et al. (1996) Neuron 17, 1005–1013 8 Citron, M. et al. (1997) Nat. Med. 3, 67–72 9 Thinakaran, G. et al. (1996) Neuron 17, 181–190 10 Hsiao, K. et al. (1995) Neuron 15, 1203–1217 11 Yankner, B. (1996) Neuron 16, 921–932
TINS Editorial Policy Trends in Neurosciences is the leading neuroscience review journal (Impact Factor 19.972; SCI Journals Citation Reports® 1995), publishing timely and wide-ranging feature articles that enable neuroscientists to keep up to date in and around their own research fields. Reviews form the foundations of each issue and offer concise and authoritative summaries of important areas of neuroscientific research; Meeting Reports and Research News articles describe recent developments within a particular field; Perspectives discuss areas of historical, social and more oblique interest – offering interesting insights into current research as it applies to neuroscience; Viewpoints include more controversial or synthetic ideas. The Debate section provides a series of alternative viewpoints on a currently hotly debated topic. Perspectives on Disease discuss how basic neurobiological studies can be applied to neurological disease; Techniques offers readers a guide to new methods and their use. TINS articles are specially commissioned by the Editor, in consultation with the Advisory Editorial Board. All submissions are subject to peer and editorial review – commissioning does not guarantee publication.
280
TINS Vol. 20, No. 7, 1997