Molecular Brain

BioMed Central

Editorial

Open Access

Starting at the endophenotype: A role for alpha-CaMKII inschizophrenia?
Paul W Frankland*1,2,3, Masanori Sakaguchi1 and Maithé Arruda-Carvalho1,3
Address: 1Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, M5G 1X8, Canada, 2Department of Physiology,
University of Toronto, Toronto, M5S 1A8, Canada and 3Institute of Medical Science, University of Toronto, Toronto, M5S 1A8, Canada
Email: Paul W Frankland* - paul.frankland@sickkids.ca; Masanori Sakaguchi - masanorisakaguchi@utoronto.ca; Maithé ArrudaCarvalho - m.arrudacarvalho@utoronto.ca* Corresponding author

Published: 10 September 2008
Molecular Brain 2008, 1:5

doi:10.1186/1756-6606-1-5

Received: 4 September 2008
Accepted: 10 September 2008

This article is available from: http://www.molecularbrain.com/content/1/1/5© 2008 Frankland et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Using an endophenotype-driven screen, a new study finds that α-calcium/calmodulin kinase II
mutant mice exhibit a range of behavioral abnormalities related to schizophrenia. Perhaps moststrikingly, this cluster of schizophrenia-related endophenotypes was associated with abnormal
neurogenesis in the adult hippocampus, raising the possibility that disrupted adult neurogenesis liesat the core of this and other psychiatric disorders.

Editorial
Schizophrenia is a chronic, debilitating form of mental illness, affecting more than 1% of the adult population [1].
Current treatments are palliative at best – reducing theseverity of symptoms rather than providing a cure – inpart, because of the paucity of our understanding of themolecular bases of this complex, polygenic disorder. A
more comprehensive understanding of the molecularunderpinnings of schizophrenia is an essential foundation for the development more effective treatments (andeventual cure).
A new study by Miyakawa and colleagues [this issue,Molecular Brain 2008, 1:6] sheds fresh light on potential
molecular mechanisms underlying schizophrenia. In theirstudy, the authors ran different lines of mutant micethrough a comprehensive behavioral test battery in orderto screen for behavioral abnormalities relevant to schizophrenia. In such a phenotypic screen, there are two criticaldecisions: First, which behaviors to focus on? As is the casewith many psychiatric disorders, schizophrenia is characterized by a bafflingly heterogeneous collection of behav-ioral symptoms. These include both positive symptoms(e.g., hallucinations, delusions, disordered thought) andnegative symptoms (e.g., anhedonia, decreased motivation, attentional problems and impaired working memory). Clearly, some of these abnormalities are uniquely
human and impossible to model in a mouse (even for themost adept mouse psychiatrist). The solution, then, is tofocus on a subset (rather than the entire constellation) of
behavioral abnormalities that are nonetheless heritable
and readily modeled in mice. Using this endophenotypedriven approach, Miyakawa and colleagues focused on
characterizing working memory, anxiety, aggression andinfradian and circadian rhythms in their mutant mice.
The second critical decision is which mice to screen?
Thousands of knockout, knockin and transgenic lines ofmice have been engineered. As screening large numbers ofmice is prohibitively time-consuming and expensive, it
makes sense to narrow down the field to a more tractable
number of players. Here, Miyakawa and colleagues took
advantage of their previous work with mice that have aforebrain-specific deletion of calcineurin (CN). They
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found that these mice exhibited abnormalities in a
number of behaviors related to schizophrenia [2], and,
therefore, in the present study they decided to screen 7mouse lines with mutations related to either CN signalingor CN-related mechanisms. Of these 7, the mice with themost striking behavioral phenotype were those carrying aheterozygous null mutation for α-calcium/calmodulin
kinase II (α-CaMKII+/- mice). These are mice with a storied
history in the field of learning and memory. Originallygenerated by Alcino Silva while a postdoctoral fellow inSusumu Tonegawa's lab at MIT, initial studies with the αCaMKII homozygous mutants helped to establish that αCaMKII plays an essential role in synaptic plasticity andhippocampal learning [3,4]. Subsequent studies using theheterozygous mutants suggested that α-CaMKII also plays
a key role in cortical plasticity, and in the consolidation of
remote memories [5,6].
In their new study, Miyakawa and colleagues found thatthe behavioral phenotype of the α-CaMKII+/- mice is more
complex (and perhaps more abnormal) than previously
appreciated. Perhaps most notably, the α-CaMKII+/- mice
have severe working memory deficits (tested either in aradial arm maze or delayed alternation task). Working
memory deficits are a core symptom of schizophrenia,
and working memory deficits have been consistently
identified in other mouse models of schizophrenia (mostrecently, for example, in mice with mutations in Disrupted-in-schizophrenia-1 [Disc1] [7,8]). Adding to this collection of psychiatric-related behavioral phenotypes,
further analyses revealed that the α-CaMKII+/- mice areunusually aggressive (killing their cage mates given half achance), less anxious and had dramatically disrupted patterns of daily activity.
Because informative endophenotypes need not be
restricted to the behavioral domain, next Miyakawa andcolleagues took a look inside the brains of the α-CaMKII+/- mice. Their analyses uncovered quite striking changes inthe dentate gyrus of the hippocampus (a brain region thatplays a key role in working memory). The dentate gyrus isa special place in the brain – it is one of two regions where
new neurons continue to be generated throughout adulthood [9]. Miyakawa and colleagues found that this process – hippocampal adult neurogenesis – was quite
abnormal in the α-CaMKII+/- mice. While more new neurons appeared to be produced (proliferation wasincreased by about 50%), these neurons did not appear tomature normally – the dentate gyrus of α-CaMKII+/- micecontained a higher proportion of granule cells with immature properties (e.g., increased excitability and reduced
dendritic branching and length). This shift in balancefrom mature to immature granule cells suggested to Miyakawa and colleagues that the α-CaMKII+/- mice have an
immature dentate gyrus.

http://www.molecularbrain.com/content/1/1/5

That changes in the regulation of neurogenesis in theadult hippocampus are associated with a cluster of behavioral endophenotypes related to schizophrenia in the αCaMKII+/- mice is particularly noteworthy. There ismounting interest in the potential role of adult neurogenesis in the pathology of a number of psychiatric illnesses,
including schizophrenia and depression [10]. For example, antidepressants may well work by increasing hippocampal neurogenesis [11] and, while adult neurogenesis
may be unaltered in depressed patients, recent reportssuggest that levels of hippocampal neurogenesis are
reduced in schizophrenic patients [12]. The emerging
hypothesis is that abnormal neurogenesis may contributeto abnormal hippocampal function [10]. Since the hippocampus is involved in regulation of mood and cognition, such aberrant hippocampal processing may
cumulatively lead to the sorts of disturbances in thought
and mood found in schizophrenia and depression. This is
an intriguing new hypothesis and, if true, suggests that in
hunting down schizophrenia susceptibility genes it mightmake most sense to pay special attention to genes that regulate neuronal development and/or adult neurogenesis.
In this regard, it is particularly exciting that perhaps thestrongest candidate schizophrenia gene – Disc1 – is implicated in neuronal migration and differentiation [13].
Consistent with this, α-CaMKII itself regulates neuronaldevelopment [14], and the expression of a large numberof genes that have been implicated in neuronal development (e.g., genes in the BDNF-MAPK pathway) were differentially regulated in the α-CaMKII+/- mice.
A final thought on the approach that Miyakawa and colleagues adopted in this study. In exploring gene-function
relationships both forward-genetic (i.e., phenotype →gene(s)) and reverse-genetic (i.e., gene → phenotype(s))
approaches have traditionally been used [15]. However,there are limitations associated with both approaches. In
forward-genetic studies (such as ENU mutagenesisscreens) identifying the causative mutation may be anespecially time-consuming and expensive process. Similarly, in reverse-genetic studies (such as those using
knockout mice) it is necessary to have a good idea about
which gene to target and such a priori knowledge may
often be lacking in complex polygenic disorders like schizophrenia. The strategy used by Miyakawa and colleagues
blurs the boundaries between these two traditional classifications. Indeed, the use this hybrid strategy – a phenotypic screen of previously engineered mutant mice – isparticularly powerful since it allows for the rapid association of schizophrenia-related endophenotypes with specific genes. A similar strategy has recently been used toidentify genes for remote memory [16]. By combining thebest of both worlds, Miyakawa and colleagues bring us astep closer to understanding the molecular basis of schizophrenia.

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Acknowledgements
PWF is supported by a CIHR Canada Research Chair in Cognitive Neurobiology. MS. and MA-C are supported by Restracomp awards from The
Hospital for Sick Children Research Institute. MA-C is additionally supported by an Ontario Graduate Scholarship award.

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