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Developmental Genes and
Regulatory Proteins, Domains of
Cognitive Impairment in
Schizophrenia Spectrum Psychosis
and Implications for Antipsychotic
Drug Discovery: The Example of
Dysbindin-1 Isoforms and Beyond
John L. Waddington
1,2
*, Xuechu Zhen
2
and Colm M. P. O’Tuathaigh
1,3
1
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland,
2
Jiangsu Key
Laboratory of Translational Research & Therapy for Neuro-Psychiatric Disorders and Department of Pharmacology, College
of Pharmaceutical Sciences, Soochow University, Suzhou, China,
3
Medical Education Unit, School of Medicine, Brookfield
Health Sciences Complex, University College Cork, Cork, Ireland
Alongside positive and negative symptomatology, deficits in working memory, attention,
selective learning processes, and executive function have been widely documented in
schizophrenia spectrum psychosis. These cognitive abnormalities are strongly associated
with impairment across multiple function domains and are generally treatment-resistant.
The DTNBP1 (dystrobrevin-binding protein-1) gene, encoding dysbindin, is considered a
risk factor for schizophrenia and is associated with variation in cognitive function in both
clinical and nonclinical samples. Downregulation of DTNBP1 expression in dorsolateral
prefrontal cortex and hippocampal formation of patients with schizophrenia has been
suggested to serve as a primary pathophysiological process. Described as a “hub,”
dysbindin is an important regulatory protein that is linked with multiple complexes in the
brain and is involved in a wide variety of functions implicated in neurodevelopment and
neuroplasticity. The expression pattern of the various dysbindin isoforms (-1A, -1B, -1C)
changes depending upon stage of brain development, tissue areas and subcellular
localizations, and can involve interaction with different protein partners. We review
evidence describing how sequence variation in DTNBP1 isoforms has been differentially
associated with schizophrenia-associated symptoms. We discuss results linking these
isoform proteins, and their interacting molecular partners, with cognitive dysfunction in
schizophrenia, including evidence from drosophila through to genetic mouse models of
dysbindin function. Finally, we discuss preclinical evidence investigating the antipsychotic
potential of molecules that influence dysbindin expression and functionality. These
Frontiers in Pharmacology | www.frontiersin.org January 2020 | Volume 10 | Article 16381
Edited by:
Adrian Preda,
University of California,
Irvine, United States
Reviewed by:
Kazutaka Ohi,
Kanazawa Medical University,
Japan
Francesco Papaleo,
Italian Institute of Technology (IIT),
Italy
Antonieta Lavin,
Medical University of South Carolina,
United States
*Correspondence:
John L. Waddington
jwadding@rcsi.ie
Specialty section:
This article was submitted to
Neuropharmacology,
a section of the journal
Frontiers in Pharmacology
Received: 28 July 2019
Accepted: 16 December 2019
Published: 29 January 2020
Citation:
Waddington JL, Zhen X and
O’Tuathaigh CMP (2020)
Developmental Genes and Regulatory
Proteins, Domains of Cognitive
Impairment in Schizophrenia
Spectrum Psychosis and
Implications for Antipsychotic
Drug Discovery: The Example
of Dysbindin-1
Isoforms and Beyond.
Front. Pharmacol. 10:1638.
doi: 10.3389/fphar.2019.01638
REVIEW
published: 29 January 2020
doi: 10.3389/fphar.2019.01638
studies, and other recent work that has extended this approach to other developmental
regulators, may facilitate identification of novel molecular pathways leading to improved
antipsychotic treatments.
Keywords: cognitive deficits, developmental gene, schizophrenia, antipsychotic drug development, dysbindin-1
INTRODUCTION
Schizophrenia, Cognitive Impairment, and
Functional Disability
Schizophrenia is a complex psychiatric disorder that is the
exemplar of a broader spectrum of psychotic illness in which
interactive contributions from genetic and environmental factors
play critical roles in etiology and pathobiology (Owen et al.,
2016); hereafter, we use the term schizophrenia as shorthand for
this spectrum of illness. In intimacy with positive, psychotic
symptoms that define this spectrum, dysfunction in working
memory, attention, processing speed, visual and verbal learning,
reward-related learning, and prominent deficits in executive
function have been extensively documented in schizophrenia
(Kahn and Keefe, 2013). Impairment across these domains, in
juxtaposition with negative symptoms, has long been accepted as
core features of schizophrenia that contribute substantively to
disability and are generally treatment refractory (Green
et al., 2019).
Several authors have recommended inclusion of cognitive
impairment in formal diagnostic criteria for this illness, as well as
highlighting the need for research on developing new and more
effective treatments to enhance cognitive abilities therein (Kahn
and Keefe, 2013;Schaefer et al., 2013;Mark and Toulopoulou,
2016). Cognitive deficits associated with schizophrenia are
observed in unaffected family members of individuals with the
disorder (Toulopoulou et al., 2019) and the presence of
schizophrenia-associated cognitive impairment in children can
predict increased risk for the illness (Meier et al., 2014;Agnew-
Blais et al., 2015).
Schizophrenia, Cognitive Impairment, and
Genetics
Twin studies continue to affirm a primary role for genetic factors
in the etiology of schizophrenia (Hilker et al., 2018), in
association and interaction with environmental adversities
(Guloksuz et al., 2019). However, despite considerable
endeavour during the past 20 years, genomic studies of
schizophrenia have arguably failed to provide the expected
answers, or have highlighted the difficulties in elucidating a
complex, heterogeneous, and polygenic genetic architecture.
The existing literature indicates contributions from multiple
common and occasional rare variants that may interact in
conferring risk for schizophrenia (Bergen et al., 2019;
Weinberger, 2019). A key challenge in this field involves the
translation of advances in our understanding of the genetics of
schizophrenia and the mechanistic basis of these associations
into tangible improvements in patient-centred care and
antipsychotic drug discovery.
In support of a common disease-common allele hypothesis,
whereby much of risk for schizophrenia is conferred via the
cumulative effect of multiple common alleles, a landmark
genome wide association study of more than 36,000 cases and
over 113,000 controls identified 108 loci for common risk
variants that achieved genome-wide significance
(Schizophrenia Working Group of the Psychiatric Genomics
Consortium, 2014). These risk variants are involved in several
known processes, including synaptic plasticity and within the
major histocompatibility complex, but also in as-yet unknown
functions. In the most recent analysis completed by the same
consortium, which involved 30,000 additional subjects, the
number of GWAS-significant loci was expanded to 246
(Weinberger, 2019).
Polygenic risk scores (PRS) represent an aggregate measure of
genetic risk as they consider the additive effects of all significant
variation across multiple genes and regulatory areas across the
entire genome (Jones et al., 2016;Xavier et al., 2018;
Toulopoulou et al., 2019). The PRS is calculated by summing
all the alleles (weighted by their individual odds ratios) that have
been associated with an illness in the latest GWAS data set for
that illness. In the most recent study of the effect of schizophrenia
risk alleles on cognition (Richards et al., 2019), schizophrenia
PRS were associated more strongly with case-control cognitive
differences as opposed to variation within cases.
Copy number variants (CNVs), both rare de novo and
inherited, make only a minor contribution to population risk
variation despite larger effect sizes (Manolio et al., 2009;
Malhotra and Sebat, 2012;Kotlar et al., 2015;Genovese et al.,
2016). In schizophrenia, these rare variants are found at loci
containing genes implicated in synaptic function as well as
neurodevelopmental processes linked with glutamatergic
function pathways (Kirov et al., 2012;Marshall et al., 2017).
Genovese et al. (2016) reported that genes implicated in synaptic
function potentially explained more than 70% of the exome
enrichment in damaging ultra-rare variants that contribute to
schizophrenia. Some authors have proposed a merging of
common allele and rare variant mechanisms, suggesting that
individuals with schizophrenia having well-characterized
pathogenic CNVs also associate with an excess burden of
common risk alleles (Tansey et al., 2016;Bergen et al., 2019).
More recent hypotheses suggest that the complex genetic
architecture of schizophrenia may be better explained in terms of
an “omnigenic”framework. This hypothesis (Boyle et al., 2017)
posits that for complex traits such as schizophrenia, GWAS may
identify genes more central to a disease process. However, these
“core”genes function in a cellular network that is associated with
the vastly more numerous other “peripheral”genes that have less
evident relationship to disease but are able to influence the
Waddington et al. Developmental Genes and Antipsychotic Drug Discovery
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function of “core”genes. Indeed, recent evidence suggests in
schizophrenia a “core”gene set that appears to contribute to risk
to a greater extent than an omnigenic background effect
(Rammos et al., 2019).
SCHIZOPHRENIA, COGNITIVE
IMPAIRMENT, AND VARIATION IN
DTNBP1
Dysbindin-1 is a coiled-coil-containing protein encoded by
DTNBP1 (Dystrobrevin Binding Protein 1, 6p22.3), a gene that
has been linked with cognitive and anatomical endophenotypes
in both patients with neuropsychiatric disorders as well as
nonclinical samples (Ayalew et al., 2012;Wang et al., 2017;
Savage et al., 2018). An initial report of genetic linkage to
schizophrenia on chromosome 6p24-22 (Straub et al., 1995)
was followed by multiple individual replications and
confirmatory meta-analyses of DTNBP1 (Allen et al., 2008;
Ayalew et al., 2012;Wang et al., 2017); any concern that such
findings have not been prominent in GWAS studies to date
(Farrell et al., 2015) must be juxtaposed with increasing
recognition that GWAS cannot in itself be considered
definitive on such issues (Tam et al., 2019;seealso
Schizophrenia, Cognitive Impairment, and Genetics above), and
that the GWAS focus on diagnosis and symptom severity scores
is likely to lead to neglect for genes specifically linked with
cognitive dysfunction in schizophrenia. Additionally, the
expression of dysbindin-1 and its isoforms is disrupted in
brain tissue from schizophrenia patients (see Schizophrenia
Pathobiology and Dysbindin Isoforms below). Importantly for
issues to be considered further below, variations in DTNBP1
associated with schizophrenia (SNPs and haplotypes) are located
in intron or promoter regions and almost all are located in the N-
terminus of the gene (Guo et al., 2008).
Several studies have investigated the role of this gene in
cognitive deficits of schizophrenia. For example, DTNBP1
haplotypes are associated with greater decline in IQ (Burdick
et al., 2007) and impairment in spatial working memory
(Donohoe et al., 2007;Donohoe et al., 2008;Donohoe et al.,
2010) and attentional/vigilance (Baek et al., 2012), verbal and
visual working memory and speed of processing (Varela-Gomez
et al., 2015), as well as executive function (Scheggia et al., 2018).
Such findings have been less evident on subdividing
schizophrenia patients into cognitive-deficit and cognitive-
sparing groups (Peters et al., 2008). Other studies have also
failed to report a relationship between DTNBP1 variants and
general tests of cognitive ability in patients with schizophrenia
and first-degree relatives compared to controls (Strohmaier et al.,
2010;Chow et al., 2018). Additionally, while some authors have
shown that DTNBP1 variation in healthy controls and patients is
associated with performance across a diverse range of cognitive
tests (e.g. Burdick et al., 2006), a meta-analysis of 11 articles
examining the relationship between dysbindin and general
cognitive ability revealed only a modest relationship (Zhang
et al., 2010). These results support involvement of the
DTNBP1 gene in selective domains of cognition rather than
non-specific cognitive ability (Luciano et al., 2009). Despite
preliminary evidence to suggest dysbindin involvement in
cognitive function in patients with brain tumours (Correa
et al., 2016), there is a paucity of studies examining the role of
dysbindin in other neurological and neuropsychiatric disorders
where symptoms include cognitive dysfunction.
SCHIZOPHRENIA PATHOBIOLOGY AND
DYSBINDIN ISOFORMS
Dysbindin expression levels vary across neuronal populations
throughout the brain and are particularly abundant in the
dentate gyrus of the hippocampal formation (Talbot et al.,
2004;Talbot et al., 2006), with dysbindin localization in the
CNS occurring in both neurons and, at comparable levels, in glia
(Ghiani et al., 2009;Shao et al., 2011). DTNBP1 encodes for three
majorspliceisoformsofdysbindin-1:1A,1B,and1C.
Dysbindin-1A is most highly concentrated in postsynaptic
density fractions and dysbindin-1B is most abundant in
synaptic vesicle fractions; similar to dysbindin-1A, dysbindin-
1C is most highly concentrated in postsynaptic density fractions;
nuclear localization has also been reported for dysbindin-1A and
-1B (Oyama et al., 2009;Talbot et al., 2011).
Sequence variation might be a mechanism by which the
function of DTNBP1 differs between schizophrenia cases and
controls. In this scenario, instead of a simple incorrectly encoded
protein, the amount of DTNBP1 expression may be affected.
Indeed, it has been shown that variations in DTNBP1 affect its
expression in the human brain (Bray et al., 2003;Bray et al., 2005;
Bray et al., 2008).
The hippocampal formation plays a fundamental role in
working and episodic memory, highlighting the possible role of
dysbindin in cognitive processes that are believed to be critical to
schizophrenia (Tamminga et al., 2010). Talbot et al. (2004) reported
that schizophrenia patients show reduction of dysbindin-1 protein
in the principal neurons of CA2 and CA3 and especially in the
dentate gyrus of the hippocampal formation. A subsequent study
from the same group reported that dysbindin proteins in the
dentate gyrus are essentially present postsynaptically (Talbot
et al., 2006). Talbot et al. (2011) then reported that in
schizophrenia patients levels of dysbindin-1B and -1C, but not
-1A, are decreased in the hippocampal formation, while levels of
dysbindin-1A, but not -1B or -1C, are decreased in the superior
temporal gyrus. Furthermore, transcripts encoding dysbindin-1B
are upregulated in peripheral bloodleukocytesofpatientswith
schizophrenia relative to controls, with an intronic DTNBP1
variant associated with schizophrenia affecting splicing and
leading to specific over-expression of dysbindin-1B (Xu et al., 2015).
Similarly to the hippocampal formation, the dorsolateral
prefrontal cortex (DLPFC) is crucially involved in working and
episodic memory, highlighting a further possible contribution of
dysbindin to cognitive deficits encountered in schizophrenia
(Lewis et al., 2008). Weickert et al. (2004) reported varying
levels of DTNBP1 mRNA within the DLPFC, with higher
Waddington et al. Developmental Genes and Antipsychotic Drug Discovery
Frontiers in Pharmacology | www.frontiersin.org January 2020 | Volume 10 | Article 16383
expression found in layers IV and V; in DLPFC of schizophrenia
patients decreases in DTNBP1 mRNA were reported in layers II,
III, V and VI, but not in layers I and IV. Subsequently, decreases
in DTNBP1 mRNA were reported in the hippocampal formation
(Weickert et al., 2008). However, a subsequent study from the
same team could not wholly confirm these findings (Fung et al.,
2011). Tang et al. (2009) reported reductions in dysbindin-1C,
but not in -1A or -1B, in DLPFC in the absence of changes in
mRNA levels of the three isoforms. It should be noted that
laminar-specific alterations in dysbindin mRNA and proteins
may have escaped detection with the homogenate-based
approach used in both studies (Tang et al., 2009;Fung et al.,
2011). More recently, dysbindin-1B, but not -1A, protein levels
were found to be higher in the DLPFC in schizophrenia
(Konopaske et al., 2018).
SCHIZOPHRENIA, NEURODEVELOPMENT,
NEUROPLASTICITY, AND DYSBINDIN
A wealth of epidemiological, clinical, and biological evidence
now indicates that the origins of schizophrenia are to be found
primarily in the early phases of fetal brain development: during
this period a variety of factors, mainly genetic but also including
environmental adversities, interact to disrupt brain
morphogenesis (Waddington et al., 2012;Birnbaum and
Weinberger, 2017); thereafter, endogenous and exogenous
factors and processes can act to further “sculpt”brain
development and maturation as a substrate from which the
diagnostic symptoms and disabilities of clinical psychosis
emerge, most typically during early adulthood (Waddington
et al., 2012;Weinberger, 2017).
Regulation of brain development involves a multitude of
genetic processes and associated proteins that act and interact
sequentially to determine “normal”adult cerebral structure and
function. Among these, dysbindin is one important regulator
that is linked with multiple complexes in the brain and numerous
diverse functions implicated in neurodevelopment and
neuroplasticity. However, while the different dysbindin isoform
proteins might interact with different partners, the majority of
studies do not provide sufficient information to confirm or refute
isoform-specific processes.
Promotion of Cell Growth, Proliferation,
and Antiapoptotic Effects
Dysbindin promotes activation of Akt (Numakawa et al., 2004),
which mediates growth and proliferation of cells (Manning and
Cantley, 2007). Akt has itself been proposed as a risk gene for
schizophrenia and a target for antipsychotic drug development
(Zheng et al., 2012;Enriquez-Barreto and Morales, 2016). Studies
have reported that dysbindin is present in neurites and in axonal
growth cones and that down regulation of dysbindin results in
aberrant organisation of the actin cytoskeleton at the tips of
neurites of differentiating cells, with shortening of such neurites
(Kubota et al., 2009;Taneichi-Kuroda et al., 2009).
BLOC-1 and Endosomal Trafficking
Dysbindin is a stable component of the multi-subunit complex
BLOC-1 (biogenesis of lysosome-related organelles complex-1;
Dell’Angelica, 2004;Li et al., 2004;Lee et al., 2012). Among the
subunits of BLOC-1, dysbindin interacts directly with pallidin,
MUTED, and snapin (Li et al., 2003;Starcevic and Dell’Angelica,
2004). Mice containing constitutive deletion of the pallidin gene
show performance deficits in two different measures of
recognition memory: the novel object recognition task and a
measure of social novelty recognition (Spiegel et al., 2015).
Studies have also reported an association between markers at
MUTED and schizophrenia (Straub et al., 2005; but see also
Gerrish et al., 2009). Moreover, both dysbindin and MUTED
siRNA increased cell surface dopamine (DA) D2 receptors (D2R)
and blocked DA-induced D2R internalization in human and rat
cells. In contrast, decreased dysbindin altered neither D1
receptors (D1R) levels nor their basal expression or DA-
induced internalisation (Iizuka et al., 2007). Such an increase
in D2R signalling could contribute to the imbalance in DAergic
neurotransmission characteristic of schizophrenia, i.e.,
hyperfunction through D2R and attenuation of such
hyperfunction by current D2R antagonist antipsychotics
(McCutcheon et al., 2019).
A recent review has comprehensively addressed the
relationship and interactions between BLOC-1 genes/proteins
and cognitive phenotypes observed in neurodevelopmental
disorders (Hartwig et al., 2018). The predominant theme is
that BLOC-1 subunits in brain areas linked to cognitive
functions are part of a more complex set of molecular
interactions, including proteins implicated in schizophrenia
such as disrupted-in-schizophrenia-1 and SNARE (Talbot,
2009;Hartwig et al., 2018).
Dysbindin and Dystrophin-Associated
Protein Complex
Dysbindin binds to the dystrobrevins, which are components of the
dystrophin-associated protein complex (DPC) (Benson et al., 2001;
but see also Nazarian et al., 2006). In the brain, several DPC-like
complexes have been implicated in cognitive impairment
commonly found in patients with Duchenne muscular dystrophy
(DMD) (Blake and Kröger, 2000). Indeed, DPC is necessary for
maturation and function of a subset of inhibitory synapses (Grady
et al., 2006). Lack of dystrophin in the mdx mouse model of DMD
produces an altered distribution of dysbindin in the brain,
suggesting a role for dysbindin-1 in the cognitive impairment
observed in DMD patients (Sillitoe et al., 2003).
NONISOFORM- AND ISOFORM-SPECIFIC
GENETIC MUTATION MODELS FOR
DYSBINDIN-1 FUNCTION
Drosophila Mutants
One dysbindin protein has been demonstrated in drosophila,
known as CG6865-PA. While the amino acid sequence of its
Waddington et al. Developmental Genes and Antipsychotic Drug Discovery
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coiled-coil domain is closely related to that of all known
orthologs of dysbindin, neither its N-terminal nor its C-
terminal region is closely related to corresponding regions in
any vertebrate dysbindin ortholog. CG6865-PA shares 28%
amino acid identity with human dysbindin-1A (Guo et al.,
2009). Drosophila dysbindin mutants demonstrate impaired
neurotransmission, disrupted synaptic homeostasis, presynaptic
and postsynaptic morphological alterations, and disruption in
short term memory (Dickman and Davis, 2009;Cheli et al., 2010;
Shao et al., 2011;Gokhale et al., 2015;Mullin et al., 2015;Gokhale
et al., 2016).
Shao et al. (2011) reported that neuronal disruption of
dysbindin function in drosophila was associated with
hypoglutamatergic transmission and deficits in working
memory, while disruption of dysbindin function in glial cells
was associated with hyperdopaminergia and locomotor
hyperactivity; this latter effects was mediated via a reduction in
the protein Ebony, a glia-specific beta-alanyl biogenic amine
synthetase involved in metabolic degradation of biogenic
amines in the nervous system. This study reveals distinct
functions of dysbindin in neurons and glial cells and highlights
the potential of new therapeutics for schizophrenia that target
glial cells (Bernstein et al., 2015). As reduction of dysbindin in
drosophila impacts on short-term memory, dysbindin-dependent
pathways may shed further light on the mechanisms of cognitive
dysfunction in schizophrenia (Larimore et al., 2014).
Mutant Mouse Models
Genetic mouse models enable etiologically related investigation
of the pathophysiology of schizophrenia, providing means to
advance target discovery to improve treatment for psychotic
illness (O’Tuathaigh and Waddington, 2015). The development
of new and effective drug therapies generally requires analysis of
the intact brain in valid preclinical models, most commonly
involving rodents (Dawson et al., 2015). Therefore, integrated
research strategies for the delineation of animal models, based on
characterization of cognitive deficits and underlying
mechanisms, have considerable translational potential
(Diamantopoulou and Gogos, 2019). In particular, based on
the role of working memory in supporting a variety of
cognitive abilities and its association with deficits in social and
occupational functioning in schizophrenia, characterization of
these processes in any mutant model is fundamental to
understanding the relevance of the experimental model to
cognitive dysfunction in this disorder.
While dysbindin-1A is highly conserved among vertebrates,
there is no ortholog of human dysbindin-1B in mice; dysbindin-
1C is a 270 amino acid protein in humans and a 271 amino acid
protein in mice (Talbot, 2009). A spontaneous deletion mutation
in DTNBP1 occurred in the DBA/2J strain, leading to complete
absence of dysbindin-1A and 1C proteins in homozygous mice
and reduced expression levels in heterozygous mice; the sandy
(sdy) coat colour of homozygous mutants gives the strain its
name (Swank et al., 1991). While the earliest studies were carried
out in mice with the original DBA/2J background (sdy/DBA), the
mutation has been transferred subsequently onto a C57BL/6J
background (sdy/B6). DBA/2J mice are homozygous for at least
six mutations, of which four are associated with neural
impairments (Cox et al., 2009;Talbot, 2009). These appear to
account for a number of auditory and visual deficits, when
compared with C57BL/6 mice.
Sandy Mice on a DBA/2J Background
Studies indicated abnormalities related to cognitive impairment
(disturbance of long-delay recognition memory during an object
recognition test) in homozygous sdy/DBA mice without
abnormalities related to basal activity levels or anxiety (Feng
et al., 2008). These authors also confirmed a previous finding of
direct interaction with and decrease in the steady-state level of
snapin (a SNAP-25 binding protein), suggesting an upstream
regulatory role of dysbindin on neurotransmitter release via
snapin. Takao et al. (2008) also reported cognitive deficits,
including impairment in long-term memory retention (Barnes
maze test) and in working memory (T-maze, forced alternation
task). Bhardwaj et al. (2009) also demonstrated deficits in short-
term memory (object recognition memory test) and stronger
dependent memory for fearful events in sdy/DBA mice. In a
subsequent study such mutants showed impaired recognition
memory in the novel object recognition and social recognition
paradigms (Spiegel et al., 2015).
Kobayashi et al. (2011) demonstrated hypersensitivity to both
serotonergic and DAergic modulation of DG-to-CA3 signal
transmission in 4-month-old to 6-month-old male
homozygous sdy/DBA mice. These authors also reported
decreased expression of D1R mRNA in the hippocampus that
could contribute to changes in synaptic modulation. Jentsch et al.
(2009) reported impaired glutamatergic transmission through
potentially both presynaptic and postsynaptic mechanisms in the
prefrontal cortex (PFC) of heterozygous and homozygous sdy/
DBA mice. While dysbindin deletion appears to decrease
glutamate release at the axon terminal, it may also result in an
increase in excitability that might be due to reduction in
neuronal dendritic branching and/or transmitter release in
GABAergic interneurons. This study also reported
homozygous sdy/DBA mice to show impairment in a spatial
working memory task (delayed nonmatch-to-position test), with
heterozygous mutants showing an intermediate level of
performance. Collectively, these results suggest that dysbindin
dysregulation might contribute to the cognitive symptoms of
schizophrenia by decreasing glutamatergic transmission, at least
in the prefrontal cortex.
Sandy Mice on a C57BL/6J Background
Studies involving the sandy mouse on a C57BL6 background also
show cognitive deficits. Cox et al. (2009) first reported
impairment in spatial memory and/or initial learning and
acquisition (Morris water maze) in sdy/B6 mice. Carlson et al.
(2011) reported reductions in sdy/B6 mice of auditory-evoked
response adaptation, prepulse inhibition, and evoked g-activity,
which is most frequently linked with disrupted inhibition and
reduction in parvalbumin (PV)-positive interneuron activity.
Indeed, subsequent analyses revealed reduction of fast-spiking
GABAergic inhibition and fewer PV cells in the hippocampus of
sdy/B6 mice.
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As previously shown in sdy/DBA mice (Jentsch et al., 2009),
homozygous sdy/B6 mice showed a decrease in working memory
performance (delayed nonmatch-to-position test) compared to
wildtypes; these results correlated with degree of expression of the
NR1 subunit of the NMDA receptor. Other studies have shown an
altered GluN2B-GluN2A switch in the hippocampus and cortex of
dysbindin mutant mice (Sinclair et al., 2016). Genetic loss of
dysbindin-1 expression has also been shown to impact on NMDA
receptor-dependent synaptic plasticity in the hippocampus in both
sdy/DBA and sdy/B6 mice (Glen et al., 2014). Another study
demonstrated that loss of dysbindin-1 leads to reduced mGluR1
signalling in the hippocampus, which is associated with altered
hippocampal synaptic plasticity in sdy/B6 mice (Bhardwaj et al.,
2015). Overall, these results suggest a role for dysbindin in the
regulation of NMDA and cognition that might be associated with
cognitive deficits in schizophrenia.
Papaleo et al. (2012) reported differences in reference memory
(T-maze) or a habituation/dishabituation task (olfactory
discrimination test) in sdy/B6 mice, which demonstrated more
rapid acquisition of a working memory task (T-maze) and overall
worse performance on the same test under more demanding
(proactive interference) or more stressful (transfer in a new cage)
conditions relative to controls. Other data from the same group
suggested that interval timing deficits may be a crucial component
of abnormal cognition in sdy/B6 mice and that these deficits might
be improved with increased training and experience (Carr
et al., 2012).
Subsequent experiments were conducted to evaluate D2R
modulation of these behavioral effects (Papaleo et al., 2012).
While chronic D2R agonist administration did not affect
acquisition in the working memory test, under more
demanding conditions this treatment impaired working
memory performance in a manner comparable to that
observed in sdy/B6 mice. These authors also reported
enhanced excitability and excitatory inputs to pyramidal
neurons in medial-PFC (mPFC) layer II/III (the layers
principally involved in intracortical projections), as well as
decreased excitatory inputs to fast-spiking GABAergic neurons
(Papaleo et al., 2012). DAergic modulation of excitatory synaptic
transmission in layer II/III pyramidal neurons involves CaM-
kinase-II (CaMKII)-dependent mechanisms that have been
implicated in learning and memory processes (Gonzalez-Islas
and Hablitz, 2003). While sdy/B6 mutants displayed lower
CaMKII and CaMKKbprotein levels in mPFC, control mice
chronically treated with a D2R agonist showed the same specific
reductions (with no change in CaMKIV and CaMKKalevels;
Papaleo et al., 2012). Overall, these results suggest that some
effects of dysbindin on cognition, associated with changes in
cortical activity and CaMK components of the mPFC, are
induced via upregulation of D2R. Consistent with a dysbindin-
associated increase in D2 receptors, dysbindin deficiency was
associated with an antipsychotic-dependent increase in the ratio
between the D2Short (D2S) and D2Long (D2L) isoforms in the
PFC of mice, which is associated with potentiation of cortical
presynaptic D2R signalling (Scheggia et al., 2018).
It has been proposed that DA signalling and PFC-dependent
cognition follow an inverted U-shaped relationship, by which
both inadequate or excessive DAergic signalling has a disruptive
effect on cognitive performance that reflects an imbalance in
dopamine D1/D2R activation (Vijayraghavan et al., 2007).
Consistent with this hypothesis, Papaleo et al. (2014)
investigated the effects on working memory performance of
simultaneous disruption of dysbindin and the gene encoding
the COMT enzyme, which plays a central role in the degradation
of DA in PFC. They showed that while disruption of either
dysbindin or COMT alone produced an improvement in
working memory performance in the discrete paired-trial
variable-delay T-maze task, mice with disruption of both genes
demonstrated impaired working memory performance. These
authors demonstrated a similar epistatic interaction on working
memory performance and accompanying activation of PFC in
humans. Based on the literature, the behavioral effects of this
genetic interaction in both human and murine working memory
paradigms reflect the effects of both genes on D1/D2R signalling
in PFC. The same authors recently reported, in both mice and
patients with schizophrenia, an interaction between functional
variation in both dysbindin and D3R genes and working memory
and executive function performance (Leggio et al., 2019).
Specifically, simultaneous reduction of D3R and dysbindin
function was associated with improved performance in tasks
accessing these cognitive domains. It was shown that this
epistatic interaction was associated with a shift in the balance
between D2R and D3R receptor expression in the PFC, leading to
an increase in D2R signalling in that brain region.
Dysbindin-1A Mutant Mice
We have recently described the generation of a genetic mouse
model with isoform-specific deletion of dysbindin-1A protein
(Petit et al., 2017). Initial phenotypic characterization showed
sexually dimorphic phenotypes, with female knockouts (KO)
being more reactive to stressful situations and male KO showing
increased exploration during initial exposure to a novel
environment that may be related to some disruption in
habituation and dysregulation of hippocampus-dependent
working memory function. No effect of genotype was observed
during acquisition or during performance in long-term
(olfactory) memory or either a conventional spatial working
memory task (spontaneous alternation) or a low-interference
delay-dependent working memory task; however, in a high-
interference task variant, male KO mutants showed
impairment in vulnerability to interference (Petit et al., 2017).
Dysbindin-1B Mutant Mice
Another recent study, which involved a transgenic mouse model
expressing the human dysbindin-1B isoform, documented the
presence of middle- and late-stage apoptosis in the hippocampus
of dysbindin-1B mutants; in a T-maze alternation task, these
mutants also showed deficits in working memory (Yang and Xu,
2017). Dysbindin-1B expression was also shown to impair spatial
learning in the Morris water maze (Yang et al., 2016).
Waddington et al. Developmental Genes and Antipsychotic Drug Discovery
Frontiers in Pharmacology | www.frontiersin.org January 2020 | Volume 10 | Article 16386
Dysbindin Gain-of-Function Mutant Mice
A further study described the behavioral phenotype of a gain-of-
function dysbindin mutant (Shintani et al., 2014). Specifically,
these authors generated a transgenic model that expressed the
human dysbindin-1A isoform. Such mutants displayed unaltered
sensory or motor behavior and no changes in anxiety,
sensorimotor gating, or exploratory behavior; they evidenced
heightened locomotor responsivity to methamphetamine and
upregulation and downregulation of several genes in PFC,
including decreases in Arc and Egr2 expression.
Spp Dysbindin Mutant Mice
Most recently, behavioral and cognitive phenotypes have been
investigated in mice containing a single point mutation in the salt
and pepper (spp) allele of DTNBP1 (Chang et al., 2018). While
spp mutants did not exhibit any deficits in working memory (T-
maze alternation task), some deficits in aspects of recognition
memoryperformancewereobserved.Thesemicealso
demonstrated a reduction in the schizophrenia-associated
SNAP-25 protein in PFC. No data are available regarding
relative isoform expression in the brains of spp mutants.
Dysbindin Mutation × Exposure to
Environmental Risk Factors
Emphasis on genetic risk factors for schizophrenia should be
tempered by evidence from investigations in twins (Hilker et al.,
2018) and epidemiological studies indicating a role for
environmental factors that may act both independently and via
gene-environment interactions (Guloksuz et al., 2019).
Therefore, animal models of neuropsychiatric disorders can
and should investigate experimental induction of/exposure to
nongenetic risk factors, including psychosocial stress and
biological insults. Though there is some debate around
common pathological mechanisms underlying the impact of
such manipulations on schizophrenia-related phenotypes
(Bradshaw and Korth, 2019), a combination of dysbindin gene
mutation and postnatal exposure to Poly I:C (a model of immune
activation in relation to schizophrenia) has been investigated. In
sdy/B6 mice, exposure to Poly I:C resulted in deficits in prepulse
inhibition and recognition memory, together with findings
contrary to expectations, such as reduced locomotion; sdy/B6
mice treated with Poly I:C also displayed attenuated contextual
and cue-dependent fear conditioning memory (Al-Shammari
et al., 2018).
DYSBINDIN-1 AND PUTATIVE
TREATMENT STRATEGIES FOR
COGNITIVE DYSFUNCTION IN
SCHIZOPHRENIA
Consistent with the proposed role for the D2R in the PFC in
mediating the putative effects of dysbindin variation on higher
order cognitive processes (Papaleo et al., 2012;Scheggia et al.,
2018;Leggio et al., 2019), a series of elegant translational studies
have shown that patients and mice with genetic variation
associated with decreased dysbindin-1 expression demonstrate
improved responsivity to the effects of antipsychotic medication
on executive function (Scheggia et al., 2018). Mechanistic
interrogation of this interaction revealed that the cognitive
response to antipsychotics was mediated by enhanced
presynaptic D2R in PFC (Scheggia et al., 2018). A subsequent
study revealed a putative role for epistatic D3R-dysbindin-1
interaction and executive function deficits in schizophrenia,
highlighting the viability of D3R modulation as a treatment
target for cognitive dysfunction (Leggio et al., 2019).
As outlined above, dysbindin disruption has also been
proposed to underlie cognitive impairment observed in
patients with Duchenne muscular dystrophy. A recent study
investigated the effects of treatment with the cacao flavonoid
(-)-epicatechin on brain dysbindin levels in the mdx mutant, a
genetic mouse model of Duchenne muscular dystrophy; such
treatment partially reversed genotype-dependent reductions in
protein levels of the dystrophin-associated protein complex as
well as dysbindin protein in PFC (Estrada-Mena et al., 2017). It
was not reported whether this partial recovery was also observed
at a behavioral level.
Investigation of transcriptional responses of developing
hippocampal neurons in sdy/B6 mutants revealed not only the
characteristic GABAergic interneuron deficiency but also
changes in expression of the cation-chloride cotransporters
NKCC1 and KCC2 during hippocampal development
(Larimore et al., 2017). NKCC1 and KCC2 expression changes
have been documented in the brains of patients with
schizophrenia (Hyde et al., 2011;Sullivan et al., 2015)and
NKCC1 agents, including the NKCC1 chloride antagonist
bumetanide, have been studied in schizophrenia. Bumetanide
reduced hallucinations in a case of schizophrenia (Lemonnier
et al., 2016) and in a randomized, double-blind placebo-
controlled clinical trial bumetanide treatment reduced
hallucinations (Rahmanzadeh et al., 2017a) but did not exert
broad antipsychotic activity (Rahmanzadeh et al., 2017b);
cognition was not specifically investigated.
Consistent with the observed involvement of dysbindin in
hippocampal and PFC glutamatergic function, a recent study
investigated the impact of pharmacological enhancement of
endogenous levels of brain-derived neurotrophic factor
(BDNF) on dysbindin-related reduction of presynaptic calcium
levels in PFC and social recognition memory in sdy/B6 mice
(Saggu et al., 2013). Systemic treatment with fingolimod, a
sphingosine 1-phosphate receptor modulator that has been
shown to increase endogenous BDNF levels, attenuated deficits
in recognition memory and sociability and in presynaptic
calcium and BDNF levels in the PFC of sdy/B6 mice (Becker-
Krail et al., 2017). BDNF levels in schizophrenia patients have
been associated with impairment across multiple cognitive
domains (Man et al., 2018;Yang et al., 2019). A recent review
has highlighted that the BDNF gene should be prioritised for
pharmacogenetic research into antipsychotic drugs and potential
relevance to treatment response and adverse effects (Han and
Deng, 2018).
Waddington et al. Developmental Genes and Antipsychotic Drug Discovery
Frontiers in Pharmacology | www.frontiersin.org January 2020 | Volume 10 | Article 16387
Similarly, administration of CDPPB, a positive allosteric
modulator of MGluR5, restored short-term recognition and
spatial memory deficits (Morris water maze) in sdy/B6 mice
(Bhardwaj et al., 2015). Given their effects on glutamatergic
signalling, and particularly on NMDA receptor activity,
MGluR5 modulators have been suggested to represent
promising treatment targets for neuropsychiatric disorders that
are characterized by cognitive deficits.
Expression of SREBP1, a sterol regulatory element binding
protein (SREBP) that regulates the expression of genes implicated
in biosynthesis of fatty acids, cholesterol, triglycerides, and
phospholipids, is reduced in sdy/B6 mice and in schizophrenia
patients; activation of SREBP1 and Arc, a protein implicated in
memory and cognition, is reduced in sdy/B6 mice and both of
these deficits were restored by treatment with clozapine,
suggesting a link with cognitive dysfunction (Chen et al., 2016).
DYSBINDIN-1 AND BEYOND
Given the indicated role for dysbindin-1 in the pathophysiology
of schizophrenia and associated cognitive impairment, it will be
heuristic to search for drug targets and molecules that might
influence its expression and functionality. Those studies that
indicate relationships between dysbindin-1 function, neuronal
and behavioral processes associated with the pathobiology of
psychotic illness and responsivity to current D2R antagonist
antipsychotic drugs are particularly provocative in this regard;
this is because they offer the prospect of clues to identifying non-
DAergic mechanisms of antipsychotic activity. Importantly,
these concepts generalize beyond dysbindin-1 to other
developmental regulators. For example, in addition to
identifying a role for dysbindin-1A in the regulation of
schizophrenia-related behavioral processes, including
specialised delay/interference-dependent working memory
(Petit et al., 2017), we have recently identified a role for the
developmental gene and regulatory protein neuregulin-1
(NRG1) in a triad with miRNA-143 and D2R that was
revealed through investigation of schizophrenia-related
behavioral abnormalities induced by phencyclidine; miRNA-
143 directly targeted to the 3’un-translated region of NRG1
mRNA to reduce protein expression of NRG1 and the D2R
modulated expression of NRG1 in PFC (Wang et al., 2019).
The issues reviewed above constitute a substantive basis for
such a search. Furthermore, they offer tantalising glimpses into
mechanisms and putative target sites relating to DTNBP1/
dysbindin-1A and how these concepts might generalize to a
broader spectrum of developmental genes and regulatory
proteins implicated in the pathobiology of schizophrenia
spectrum psychosis.
AUTHOR CONTRIBUTIONS
JW, XZ, and CO’T reviewed the relevant literature and wrote this
paper. JW, XZ, and CO’T revised the manuscript. All the authors
listed agreed to the publication of this paper.
FUNDING
This work was supported by Science Foundation Ireland through
grant 07/IN.1/B960.
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