REVIEW

Acta Neurobiol Exp 2018, 78: 210–219

DOI: 10.21307/ane‑2018‑019

The role of DSCAM in the regulation of synaptic plasticity:

possible involvement in neuropsychiatric disorders
Katarzyna Stachowicz

Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland,

Email: stachow@if-pan.krakow.pl

Synaptic plasticity simply put, is the activity‑dependent modification of the strength or efficacy of synaptic transmission in the network of
synapses in the brain. The role of synaptic plasticity in disease is an active area of research. Changes in plasticity translate to the release
of neurotransmitters at the synapse and subsequently, the way humans see the world. It is known that neuropsychiatric disorders
such as depression, posttraumatic stress disorder (PTSD), and Alzheimer’s disease (AD) are related to pathological changes in dynamic
processes in synapses, dialogue between neurons, and finally, changes in overall plasticity. To find a cure for these plasticity related
diseases, it is imperative that we understand the precise mechanisms that perturb the homeostatic balance leading to the disease state.
The aim of this review is to present what is currently known about DSCAM (Down Syndrome Cell Adhesion Molecule) a protein that is
directly connected to pathological changes in synaptic plasticity. The review will present information on DSCAM and how it is connected
to glutamate (Glu) and γ‑Aminobutyric acid (GABA) neurotransmission pathways. Finally, the review throws some light on the possible
involvement of DSCAM in a spectrum of psychiatric disorders apart from Down syndrome (DS).

Key words: DSCAM, Glu, GABA, synaptic plasticity, Down syndrome, mood

INTRODUCTION of potential sites for the occurrence of plasticity (Cram‑

er and Galdzicki 2012).
In 1949, Donald Hebb postulated that strong inter‑ Cell Adhesion Molecules (CAMs) are known partici‑
actions existed between communicating synapses, a re‑ pants in the process of forming synaptic connections,
mark often presented as: “Fire together, wire together” together with other cell surface recognition molecules
(Hebb 1949). Synaptic plasticity is a language of neuro‑ they take part in the processes of homophilic and het‑
nal communication and depends on timing, the strength erophilic bindings, fasciculation, and defasciculation
of pre‑ and postsynaptic dialogue, and the structure of (Hattori et al. 2008). Down Syndrome Cell Adhesion
dendritic spines (Cramer and Galdzicki 2012, Dan and Molecule (DSCAM) is an important factor in the process
Poo 2006). The process of synapse strengthening in‑ of synapse strengthening and the timing of synaptic
© 2018 by Acta Neurobiologiae Experimentalis

volves several factors, including the formation of new dialogue transmission (Li et al. 2009). Often, synapse
dendritic spines, modification of existing synapses dialogue is discussed in terms of long‑term potentia‑
through receptor variation, silent synapse activation, tion (LTP) and/or long‑term depression (LTD). LTP is
changes in the size or shape of the synapse, and chang‑ a long‑lasting enhancement of synaptic efficacy and is
es in the timing and levels of neurotransmitter release a predictor of synaptic plasticity, as well as a learning
(Kossut 2007). The number of spines, their localization, and memory sensor. Both processes are strictly linked
and the shape of individual spines are important factors to glutamate (Glu) activation.
in this process (Alves‑Sampaio et al. 2010). Any disrup‑ Pathological changes in the dynamic processes that
tion to this communication path results in the reduction occur at synapses coupled with neurotransmission shifts

Received 8 March 2018, accepted 9 July 2018

Acta Neurobiol Exp 2018, 78: 210–219 DSCAM 211

are characteristic features of many neuropsychiatric pathophysiology of neuropsychiatric disorders? 2) Is the

diseases. In addition, characteristic changes in DSCAM DSCAM protein/gene only an “observer” of the changes
levels are observed. Although DSCAM plays unquestion‑ in equilibrium, or an active player? To accurately answer
able roles in the different steps of neural circuit forma‑ these questions, we need to have a precise view of all
tion (Alves‑Sampaio et al. 2010), dendritic tree forma‑ changes that take place in Down syndrome (DS) – the
tion and synaptogenesis (Hortsch and Umemori 2009, best model of disturbed plasticity and learning poten‑
Jia et al. 2011, Pérez‑Núñez et al. 2016, Schmucker and tial, with a characteristic decrease in dendritic branch‑
Chen 2009, Zhu et al. 2006), the more interesting ques‑ ing and spine density in the hippocampus and cortex in
tions to ask are: 1) How does this knowledge help us in parallel to overexpressed DSCAM (Alves‑Sampaio et al.
understanding synaptic plasticity and its role in the 2010, Ferrer and Gullotta 1990, Sterne et al. 2015).

Function

Cadherins Integrins Selectins IgSF

– surface glycoproteins – heterodimers – first step of adhesion – cell surface receptors

– calcium dependent – transmembrane linkers: – the attachment of leukocytes and cell adhesions
– cell‑cell adhesion extracellular matrix and actin to the wall DSCAM
– tissue patterning cytoskeleton L‑selectins are expressed on NCAMs
– cancer circulating leukocytes ICAMs
P‑selectins – on endothelial cells VCAMs
and granules of platelets PECAM‑1
E‑selectins – induced by IL‑1, LPS, ESAM
TNF on vascular endothelial cells – function mainly in
the immune system
– cell‑cell reorganisation

(Kourtidis et al. 2017, Bajnok et al. 2017, Springer 1994, Alberts et al. 2002, Harpaz and Chothia 1994, Giancotti and Ruoslathi 1999, Wong et al. 2012).

Fig. 1. Classification and function of Cell Adhesion Molecules (CAMs).

212 K. Stachowicz Acta Neurobiol Exp 2018, 78: 210–219

DSCAM – a Down Syndrome Cell Adhesion Molecule patterns compared to DSCAM during development and
in adult mice, e.g. DSCAM shows strongest expression in
The DSCAM gene is located on human chromosome the pyramidal neurons of the cortex layers 3 and 5 (Bar‑
21 (21q22.2–q22.3), which is strictly associated with DS low et al. 2002).
(Edelman and Crossin 1991, Head et al. 2007, Yamakawa Both forms of DSCAM are expressed in the hippo‑
et al. 1998). A second DSCAM gene is located on chro‑ campus (with higher expression in the dentate gyrus
mosome band 11g23 (DSCAML1), where it is associated and Ammon’s horn) and in the olfactory bulb (Barlow et
with Tourette’s syndrome (Agarwala et al. 2001). DSCAM al. 2002). Apart from its expression in the brain of adult
belongs to the immunoglobulin superfamily of cell ad‑ mice, DSCAML1 is also expressed in tissues such as the
hesion molecules (Ig‑CAMs) (Yamakawa et al. 1998) and heart, spleen, lungs, kidneys, and testis (Barlow et al.
is a cell surface transmembrane receptor (Hortsch and 2001, Barlow et al. 2002). In humans, both DSCAM and
Umemori 2009). Cell adhesion molecules (CAMs) medi‑ DSCAML1 are expressed in the hippocampus, amygdala,
ate cell‑to‑cell and/or cell‑to‑extracellular matrix in‑ thalamus, caudate nucleus, and corpus callosum (Bar‑
teractions and are predominantly classified as integrins, low et al. 2002, Yamakawa et al. 1998). Overexpression
selectins, cadhedrins and the immunoglobulin super‑ of DSCAM has also been documented in the brains of hu‑
family (IgSF) (Wong et al. 2012). Besides DSCAM, oth‑ man patients with DS (Bahn et al. 2002, Head et al. 2007,
er IgSF members include: NCAM (Neural Cell Adhesion Sterne et al. 2015). Saito et al. (2000) reported the pres‑
Molecule, CD56), ICAM (Intracellular Adhesion Molecule, ence of DSCAM in the cerebellar white matter of control
CD54), VCAM (Vascular Cell Adhesion Protein 1) and PE‑ and DS patients and suggested DSCAM may play a role in
CAM‑1 (Platelet Endothelial Cell Adhesion Molecule, regulating myelination.
CD31) (Wong et al. 2012), (see Fig. 1 for classification and
function of CAMs).
DSCAM is one of the largest IgSF proteins (220kDa);
it is composed of an N‑terminal signal peptide, 10 im‑
munoglobulins (Igs) and 6 fibronectin type III (FNIII)
domains, a transmembrane domain (TM) and a cyto‑
plasmic tail (Hortsch and Umemori 2009, Jin et al. 2013,
Yamakawa et al. 1998). The tenth Ig domain is separat‑
ed by the fourth and fifth FNIII domains. The domain
structure composition of DSCAM is truly unique and dif‑
ferentiates it from other members of the IgSF (Hortsch
and Umemori 2009). A single membrane‑spanning do‑
main links the extracellular domain with the cytoplas‑
mic fragment of DSCAM (Hortsch and Umemori 2009).
The cytoplasmic fragment of DSCAM is composed of
300‑400 amino acids with high level of tyrosines serv‑
ing as a binding site for the SH2 domain of dedicator
of cytokinesis (Dock) proteins or the postsynaptic den‑
sity protein (PDZ) domain binding‑site (Hortsch and
Umemori 2009) (Fig. 2).
DSCAM transcripts are subject to alternative splicing
and therefore can generate various tissue‑specific pro‑
tein isoforms (Hortsch and Umemori 2009). DSCAM was
found in the neurons of the central nervous system (CNS)
and peripheral nervous system (PNS) during the mouse
developmental period. Precisely, DSCAM expression was
detected in tissues such as the liver, lungs, limb, and Fig. 2. Structure of DSCAM.
buds only during the developmental period (Agarwala et DSCAM is a transmembrane receptor, Ig‑CAM protein. The Structure of
al. 2001). It is equally expressed in the cortex, olfactory DSCAM is composed of 10 Ig domains, and 6 fibronectin type III (FN III)
domains, tandemly arranged. The DSCAM family consists of 2000
bulb, dentate gyrus, hippocampus (CA1, CA3), thalamus,
amino acids, with an average molecular weight of 220kDa. Extracellular
and cerebellum of the adult mouse brain (Agarwala et domain units are connected with the cytoplasmic region of DSCAM by
al. 2001). More precisely, DSCAM receptors were found a membrane‑spanning domain. DSCAM cytodomains contain various
on the dendrites and axons of neurons (Hortsch and tyrosines, which are binding sites for i.e. Src Homology 2 (SH2) domain
Umemori 2009). DSCAML1 shows differential expression (Docks) and PDZ domain‑binding (Hortsch and Umemori Eds 2009).
Acta Neurobiol Exp 2018, 78: 210–219 DSCAM 213

Although DSCAM has been shown to be essential in Furthermore, specific presynaptic bouton enlarge‑
the organization of the nervous system, dendritic tree ments and the presence of a great number of vacu‑
formation and synaptogenesis (Hortsch and Umemori oles and multivesicular bodies in spines were found
2009, Jia et al. 2011, Pérez‑Núñez et al. 2016, Schmucker in Ts65Dn mice (Belichenko et al. 2004). Characteristic
and Chen 2009, Zhu et al. 2006), some controversy still changes in hippocampus inhibitory synapse position
exists in the field concerning its role in the CNS. The from shafts onto the necks of dendrites were also doc‑
paragraphs that follow will attempt to shed more light umented in these mice (Belichenko et al. 2004, Cramer
on its role in the CNS based on its role in DS and non‑DS and Galdzicki 2012). Deficits in cognitive tests were
conditions. Furthermore, its connection with major neu‑ found to be linked to reduced hippocampal volumes
rotransmission pathways will be discussed. (Cramer and Galdzicki 2012). Furthermore, exagger‑
ation of inhibition in the trisomic hippocampus was
documented (Ts65Dn) (Cramer and Galdzicki 2012). In
DSCAM in DS and other conditions a parallel study, Alves‑Sampaio et al. (2010) showed
that DSCAM plays a functional role in dendritogene‑
Down syndrome sis and synaptic plasticity. Using a plasmid encoding
DSCAM‑IRES‑GFP, the authors showed significantly
DS is an outcome of trisomy of human chromo‑ reduced neurites crossing, using Sholl morphometric
some 21, the most common reason of genetic mental analysis, and reduced total dendrite length in hip‑
retardation (Alves‑Sampaio et al. 2010, Antonarakis et pocampal DSCAM‑overexpressing neurons. Further‑
al. 2004). Although a considerable amount of individ‑ more, the hippocampus of Ts1Cje mice had increased
ual variability exists in persons with DS, they exhibit levels of DSCAM mRNA and protein (Alves‑Sampaio et
a characteristic intellectual disability, with decreased al. 2010).
IQ score and speech problems that get worse during ag‑
ing (Hickey et al. 2012, Weijerman and Winter 2010).
Morphologically decreased brain size, aberrant gyrifi‑ Mood related disorders
cation, and disturbed neurogenesis are also observed
(Lockstone et al. 2007, Mrak and Griffin 2004). As an Neuronal atrophy and cognitive deficits are
outcome of reduced brain size, reduced volumes of ce‑ also known characteristics of depression and other
rebral gray and white matter are observed (Pinter et al. stress‑mediated disorders (Yu et al. 2011). Stress‑me‑
2001). At the same time, larger subcortical and parietal diated changes in neuroplasticity in the dentate gy‑
gray matter and temporal white matter are present, rus have been proposed to play significant roles in the
which according to Pinter et al. (2001) may be the cause pathophysiology of depression, despite some critical
of verbal memory deficits, and changes in short‑term reports (Liu et al. 2017). Reductions in dendrite arbor‑
visuospatial memory. Cognitive deficits in DS persons ization and spine density have been reported in the
comprise of long‑term memory changes and difficulty cortex of postmortem brains of depressed patients
in the assimilation of new skills (Pennington et al. 2003, (Banasr et al. 2011, Rajkowska and Miguel‑Hidalgo
Yu et al. 2010). 2007). Early life stress is an accepted factor in pro‑
In DS persons, dendritic branching and spine densi‑ ducing neuropsychiatric changes during adolescence,
ty are diminished both in the hippocampus and cortex as well as being linked to reduced dendritic length,
(Alves‑Sampaio et al. 2010), with changes in the mor‑ branching, and spine density in the limbic structures
phology and volume of these structures. Ferrer and and prefrontal cortex (Brenhouse and Andersen 2011,
Gullotta (1990) reported a 15% decrease in DS hippo‑ Lupien et al. 2009). Loss of spines and withdrawal of
campal spines. Similar morphological changes have also dendrites of pyramidal neurons of the prefrontal cor‑
been reported in mouse models of DS (Ts65Dn and Ts1Cje tex in rodents is common in chronic stress (Banasr et
mice). Both models show similar phenotypes and char‑ al. 2011, Radley et al. 2004). Importantly, antidepres‑
acteristic morphological changes, although obtained by sant drugs are effective as neuroplasticity enhancers
different chromosomal manipulations. Because this is (Banasr et al. 2011, Eyre and Baune 2012). Further‑
not a major focus of this study, readers can review Olson more, Amano et al. (2008) found an association be‑
et al. (2004) or Belichenko et al. (2015) for detailed infor‑ tween increased DSCAM expression and bipolar disor‑
mation on both models. der in a gene screen of patients with bipolar disorder
Decreased spine densities and increased spine vol‑ (manic‑depressive disorder). Postmortem examina‑
umes in the neocortex and hippocampus were found in tion of brains from bipolar subjects carrying the G al‑
the Ts65Dn mouse model of DS (Belichenko et al. 2004, lele of DC141 SNP, showed elevated levels of DSCAM
Siarey et al. 2006). (Amano et al. 2008).
214 K. Stachowicz Acta Neurobiol Exp 2018, 78: 210–219

Posttraumatic stress disorder (PTSD) not uncommon after 20‑years or later in the life of DS
persons (Myers and Pueschel 1991). Some DS persons de‑
Results obtained in the screen of genes in the glu‑ velop AD with dementia later in life; while some have
cocorticoid receptor (GR) pathway and genes of the evidence of AD neuropathology but may not develop de‑
neural stress response in PTSD patients (male veter‑ mentia (Head et al. 2007). Chromosome 21 links DS with
ans), found low levels of expression of DSCAM in the familial AD (St George‑Hyslop et al. 1987). DS is a result
test group compared to controls (Logue et al. 2015). In‑ of trisomy 21, with triplication of other genes, e.g. the
terestingly, a parallel decrease in BDNF expression was APP gene, leading to increased Amyloid‑β (Aβ) levels
also observed in these patients (Logue et al. 2015). It is in the brain, which is a characteristic neuropatholo‑
very interesting to note that DSCAM is downregulated gy of AD (Doran et al. 2017). In familial early‑onset AD,
in PTSD, where individuals may not forget the traumat‑ a duplication of the APP genomic locus may occur that
ic events in their lives. is known as partial trisomy of chromosome 21 (PT21),
with absence of the clinical symptoms characteristic of
DS (Doran et al., 2017, Sleegers et al. 2006).
Alzheimer’s disease (AD) Doran et al. (2017) suggests that APP is critical to the
pathogenesis of AD in DS, as DS patients normosomic for
Mental retardation presents the direct opposite of APP showed very slow cognitive loss. Imaging studies
PTSD with an upregulated level of DSCAM. Dementia is using PET suggest compensatory increases in metabolic

Table I. Main changes observed in Down syndrome, Alzheimer disease, depression and PTSD – comparative study.

Down
Alzheimer disease Depression PTSD References
syndrome

DSCAM ↑ protein/human/ ↑ APP transgenic ↑ (bipolar)serum and ↓ gene/human/ (Saito et al. 2000,
brain mice/brain/gene/ postmortem brain/ blood Jia et al. 2011,
protein human/gene Amano et al. 2008,
Logue et al. 2015)
Spine density/ ↓ spine numbers/ ↓ dendritic spines/ ↓ rats dendric spine ↓ PTSD patients/mice (Kurt et al. 2004, Chen
dendritic branching Ts65Dn Hp/Cx density Hp (CA1,CA3); (type‑dependent) et al. 2012, Dorostkar
DG et al. 2015, Norrholm
↑ mice/Hp and Ouimet 2001,
spine heads/Hp Madder 2017,
Young et al. 2015)
Cortico ↑ Ts65Dn mice large ↑ Hp culture ↑ human/serum ↕ PTSD (Martίnez‑Cué et al.
‑sterone group housing 2005, Wuwongse et
↔ patients/mice al. 2013, Pariante
and Lightman 2008,
Madder 2017,
Otte et al. 2005)
B

LTP ↓ Hp/Ts65Dn ↓ Hp/APP mice/ ↓ rats/Hp ↑ biphasic/Hp/Am/ (Siarey et al. 1999,

human Cx rats Chapman et al. 1999,
Koch et al. 2012, Liu
et al. 2017, Akirav and
Richter‑Levin 1999)
Glu ↔ fetus/Cx ↓ Human/Cx/ ↑ (bipolar/MDD) ↑ Hp/rats (Whittle et al. 2007,
HPLC Fcx Am/Hp/human Gueli and Taibi
Reuptake Hp 2013, Zhang et al.
2016, Li et al. 2011,
Hashimoto et al.
2007, Gao et al. 2014,
Friedman et al. 2014)
GABA ↓ fetus/Cx ↓ Human/Cx/ ↓ (bipolar)serum ↑ Hp/rats (Whittle et al. 2007,
HPLC human Gueli and Taibi 2013,
Li et al. 2016,
↑ Hp/HPLC/ Petty et al. 1993,
Astrocytes Gao et al. 2014)

↑ ↓ increase, decrease, ↕ different results – increase and decrease, ↔ no difference or difficult to assess.
Hp – Hippocampus, Am – Amygdala, Cx – Cortex, DG – Dentate Gyrus, FCx – Frontal Cortex, PTSD – Post Traumatic Stress Disorder, Ts65Dn – mouse Down Syndrome model,
APP – mouse Alzheimer’s Disease model.
Acta Neurobiol Exp 2018, 78: 210–219 DSCAM 215

rate in vulnerable brain regions in DS prior to the de‑ Dscam‑mediated signaling by induction of long‑term
velopment of dementia (Head et al. 2007). In fact, Head facilitation (LTF) is needed during learning‑related syn‑
et al. (2007) found DSCAM localization in cores and pe‑ apse formation (Li et al. 2009). LTF induced by a series
ripheral fibers linked to senile plaque formation in DS of 5‑HT pulses was shown as an increase in NMDA and
with AD. Amyloid precursor protein (APP) transgenic AMPA receptors at the Aplysia sensory‑motor neuron
mice (a model of AD) showed a significantly higher level synapse, 12 h post factum and was Dscam‑dependent (Li
of DSCAM expression in the cerebral cortex, compared et al. 2009). The following processes were Dscam‑depen‑
with the control wild‑type group (Jia et al. 2011). It was dent: remodeling of AMPA receptors, stabilization and
speculated that the observed effect was a leading cause formation of new synaptic connections (Li et al. 2009).
of learning, memory, sensory perception and voluntary The influence of NMDA on DSCAM expression
movement deficits in APP transgenic mice (Jia et al. has been confirmed in mouse studies. Incubation of
2011). In the mouse model of AD (APP transgenic mice), wild‑type hippocampal neurons with NMDA resulted
the DSCAM level was found to progressively increase in increased locally translated dendritic DSCAM pro‑
with age (Jia et al. 2011). However, APP and DSCAM asso‑ tein levels (Alves‑Sampaio et al. 2010). This effect is
ciations seen both in DS persons and AD models should absent in Ts1Cje hippocampal neurons, where basally
be considered as more complex than additive effects increased DSCAM levels are observed (Alves‑Sampaio
of potentially overexpressed proteins. Since AD mouse et al. 2010). Moreover, elevation of DSCAM protein level
models show microglial and astrocytic activation, with in both wild‑type and Ts1Cje hippocampal neurons was
increased levels of cytokines and cyclooxygenase‑2 abolished by treatment with an NMDA antagonist (APV)
(COX‑2) (Birch et al. 2014), while DSCAM represents an (Alves‑Sampaio et al. 2010). In turn, DSCAM‑mediated
IgSF member (Wong et al. 2012), implication of the in‑ mechanisms may be important factors during changes
flammatory response should be considered in that con‑ in synaptic plasticity, where earlier history of synapse
text. In fact, our data found engagement of COX‑2 in the activity is an important factor.
regulation of DSCAM levels in the mouse brain (unpub‑ The contribution of NMDA receptors to neuropsy‑
lished data). chiatric disorders is well‑known. Ketamine, an NMDA
The proportion of DSCAM, corticosterone levels and antagonist, is capable of producing rapid antidepres‑
changes in spine density in DS and neuropsychiatric dis‑ sant effects in humans (Banasr et al. 2011). Ketamine
orders discussed above are shown in Table IA. Because also produces rapid therapeutic effects for bipolar de‑
changes in plasticity are strictly linked to fluctuations in pression and patients with suicidal ideation (Banasr et
interactions between neurotransmitters, including tran‑ al. 2011, Grady et al. 2017) and this is particularly rel‑
scriptional and translational changes, the remainder of evant because Amano et al. (2008) demonstrated in‑
the review will focus on such signaling pathways, with creased DSCAM levels in bipolar patients. While a pos‑
particular attention to the involvement of DSCAM. sible connection between DSCAM and bipolar disorder
was suggested in this study, because of its ethnic under‑
tone further studies are needed to validate the findings.
Glutamate, GABA and DSCAM expression The therapeutic target of ketamine is known, being the
mammalian target of rapamycin (mTOR) (Banasr et al.
Studies on DSCAM and its interaction with neu‑ 2011). Postmortem studies of depressed patients found
rotransmitters are mostly based on animal models. Li a potential association between mTOR signaling activity
et al. (2009) suggested that Dscam‑mediated signaling and deficits in synaptic proteins (Jernigan et al. 2011).
was substantially involved in Glu receptor changes. Us‑ The fast antidepressant‑like effect of ketamine was dis‑
ing the Aplysia culture model, Li et al. (2009) document‑ played with increased hippocampal and prefrontal corti‑
ed Dscam‑mediated trans‑synaptic interactions acting cal mTOR and brain‑derived neurotrophic factor (BDNF)
through α‑amino‑5‑hydroxy‑3‑methyl‑4‑isoxazole pro‑ levels (Zhou et al. 2013). The increased synthesis of
pionic acid (AMPA) receptors. For clustering of AMPA re‑ BDNF was proposed as a mechanism to block the NMDA
ceptors, during de novo synapse formation, a presynaptic receptor (Szewczyk et al. 2012). Furthermore, chronic
input is required. Li et al. (2009) abolished both synap‑ antidepressant treatment resulted in increased BDNF
tic transmission and AMPA‑like receptor clustering, by levels (Duric and Duman 2013).
blockade of pre‑ and postsynaptic Dscam. At the same Viewed in the context of learning and memory for‑
time NMDA‑like receptor clustering was found to be mation, (Banasr et al. 2011, Hoeffer and Klann 2010) the
Dscam independent (Li et al. 2009). Dscam not only sta‑ dendritic presence of mTOR signaling elements is very
bilizes presynaptic structures at postsynaptic sites but important (Jernigan et al. 2011). The hyperactivation of
is required for precise wiring during synapse formation the Akt‑mTOR pathway is a characteristic outcome of DS
in the learning process (Li et al. 2009). Revitalization of disability (Troca‑Marίn et al. 2012). The Ts1Cje model of
216 K. Stachowicz Acta Neurobiol Exp 2018, 78: 210–219

DS manifested increased phosphorylation of Akt‑mTOR feedback loop for GABA/BDNF during early develop‑
as a result of increased levels of pro‑BDNF and BDNF ment has been proposed (Obrietan et al. 2002). GABA is
(Troca‑Marίn et al. 2012). It is known that DS individ‑ regarded as an important factor in cognitive and mood
uals exhibit an age‑related increase in BDNF levels (Do‑ disorders and is proposed as one of the main inhibito‑
gliotti et al. 2010). Studies on mouse DS models suggest ry factors in Ts65Dn mouse plasticity (Costa and Grybko
that impaired hippocampal synaptic plasticity coupled 2005). In Ts65Dn mice, there is an increased presence of
with impaired local translation is an outcome of basal‑
ly saturated NMDA signaling, and loss of synaptic sen‑
sitivity as a result of changes in Glutamate/BDNF (Tro‑
ca‑Marίn et al. 2012). One of the steps in this direction is
increased local translation of dendritic mRNA e.g. Dscam
(Alves‑Sampaio et al. 2010, Troca‑Marίn et al. 2012).
Based on Aplysia research, Li et al. (2011) proposed
Dscam‑ran trans‑synaptic signaling as necessary for the
occurrence of long‑term synaptic plasticity (LTP). Fur‑
thermore, it is known that during synapse formation lo‑
cally induced synthesis of new proteins and structural
modifications are generated, which are then important
factors in the back‑modulation of synaptic plasticity
(Kossut 2007). According to Belichenko et al. (2004) pre‑
synaptic terminals and dendritic spines are enlarged in
Ts65Dn mice accompanied by thickening of the post‑syn‑
aptic density of the CA1 region of the hippocampus (Kurt
et al. 2004). Taking these all into consideration, the im‑
portant factor in DSCAM‑ran trans‑synaptic signaling, is
its ability for binding the cytoplasmic fragment with the
PDZ domain binding‑site (Hortsch and Umemori 2009).
Such interactions between PSD‑95/Dscam have been
reported in the vertebrate retina (Yamagata and San‑ Fig. 3. Schematic drawing of DSCAM localization on a glutamate synapse.
es 2010). If these interactions were universal, it would Following Li et al. (2009), Dscam is a first‑step safeguard in a whole cascade
open a wide range of possibilities for DSCAM‑dependent of events during glutamate synapse communication (A). It not only
signaling at the level of modulation of glutamate recep‑ stabilizes the pre‑synaptic part to the post‑synaptic but is a guarantor of
tors, in addition to, NMDAR and metabotropic glutamate precise timing during this process. When pre‑synaptically Glu is released,
receptors (mGluRs). Fig. 3 depicts the proposed role of timed with depolarization, Mg 2+ ions are released and binding of Glu to
DSCAM/Dscam, in the cascade of events during synaptic the post‑synaptic part occurs, allowing permeation of Ca 2+ ions (Pochwat
et al. 2014). NMDA is composed of three main groups of subunits:
plasticity changes (including research in Aplysia).
GluN1, GluN2 (GluN2A, GluN2B, GluN2C, GluN2D) and GluN3 (GluN3A,
Considering the important role of DSCAM in Glu re‑ GluN3B) (Paoletti et al. 2013). It was documented, that during LTP a larger
ceptor modulation, an important question to ask would involvement of GluN1/GluN2A in total activity takes part (Paoletti et al.
be, what role does it play in GABA signaling? GABA‑ 2013). In opposition, LTD‑engages mostly GluN1/GluN2B subunits (Paoletti
γ‑Aminobutyric acid is the main inhibitory neurotrans‑ et al. 2013). Ca 2+ entry through NMDA receptors, or release by activation of
mitter in the human brain (Sibley et al. 2007). GABA is metabotropic receptors, activates intracellular signaling pathways: inositol
synthesized from L‑glutamate by L‑glutamic acid de‑ triphosphate (IP3), activation of CaMKII and insertion of GluR‑1 AMPA
receptor into the post‑synaptic membrane. This process involves Dscam,
carboxylase (GAD) (Sibley et al. 2007). A shift in balance
as Li et al. (2009) documented its role in AMPA receptor stabilization (B).
between Glu and GABA is a well‑documented factor in Furthermore, DSCAM protein level is regulated by NMDA‑dependent
the pathophysiology of many psychiatric diseases (Pilc synaptic activity and regulation is lost in trisomic neurons. The whole
et al. 2008). GABA acts through three classes of receptors cascade of events is engaged in signaling, from the synapse to the nucleus,
(GABAA, B, and C) (Sibley et al. 2007). if gene transcription has to occur (mitogen activated protein kinase (MAPK),
GABAA receptors are present at inhibitory synapses cAMP‑responsive element binding protein (CREB). CREB activation seems
both on dendrites, cell bodies, pre‑, post‑ and extra‑syn‑ to be most important step in this cascade, initiating protein synthesis and
leading to occurrence of LTP. One of the early genes in the process of
aptically (Sibley et al. 2007). An important but often for‑
synaptic plasticity is brain‑derived neurotrophic factor (BDNF). Increased
gotten fact is that GABA plays an inhibitory function in BDNF release is connected with activation of AMPA and mTOR pathways.
the adult brain while at the same time being a fast‑excit‑ These pathways are disrupted in DS persons, as Troca‑Marίn et al. (2012)
atory neurotransmitter in the immature brain (Obrietan showed increased local translation of BDNF, with greatest AMPA receptor
et al. 2002). Furthermore, the existence of a positive delivery and occurrence of an excitatory loop.
Acta Neurobiol Exp 2018, 78: 210–219 DSCAM 217

GABA‑ergic interneurons in the hippocampus and cor‑ REFERENCES

tex resulting in a GABA‑ergic imbalance (Contestabile
et al. 2017). Blockade of GABAA receptors in the hippo‑ Agarwala KL, Ganesh S, Tsutsumi Y, Suzuki T, Amano K, Yamakawa K
campus of these mice may reverse LTP impairment and (2001) Cloning and functional characterization of DSCAML1, a novel
cognitive efficiency (Cramer and Galdzicki 2012). Immu‑ DSCAM‑like cell adhesion molecule that mediates homophilic intercellu-
lar adhesion. Biochem Biophys Res Commun 285: 760–772.
nohistochemical study of the dentate gyrus in Ts65Dn
Akirav I, Richter‑Levin G (1999) Biphasic modulation of hippocampal plas-
mice showed a shift of GABA‑ergic synapses to the spine ticity by behavioral stress and basolateral amygdala stimulation in the
necks, which may contribute to impairment of synaptic rat. J Neurosci 19: 10530–10535.
integration (Contestabile et al. 2017). Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002) Molecular
Glutamate/GABA‑ergic imbalance was also suggest‑ biology of the cell, 4th edn. New York: Garland Science. Ann Bot 91:
401.
ed as the cause of cognitive behavioral changes in PTSD,
Alves‑Sampaio A, Troca‑Marín JA, Montesinos ML (2010) NMDA‑mediated
DS, depression, and AD (Contestabile et al. 2017, Costa regulation of DSCAM dendritic local translation is lost in a mouse model
and Grybko 2005, Gao et al. 2014, Li et al. 2016, Pilc et of Down’s syndrome. J Neurosci 30: 13537–13548.
al. 2008). It is now well known that neural cell adhe‑ Amano K, Yamada K, Iwayama Y, Detera‑Wadleigh SD, Hattori E, Toyota T,
sion molecules (NCAMs) influence GABA‑ergic synapse Tokunaga K, Yoshikawa T, Yamakawa K (2008) Association study be-
tween the Down syndrome cell adhesion molecule (DSCAM) gene and
specificity (Sassoè‑Pognetto et al. 2011). IgSF9b, a syn‑
bipolar disorder. Psychiatr Genet 18: 1–10.
aptic adhesion molecule is highly expressed in inhib‑ Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S (2004) Chro-
itory synapses of the hippocampus, cortical neurons, mosome 21 and down syndrome: from genomics to pathophysiology.
and GABA‑ergic interneurons. More importantly, it Nat Rev Genet 5: 725–738.
plays a role in major depressive disorder (Shyn et al. Bahn S, Mimmack M, Ryan M, Caldwell MA, Jauniaux E, Starkey M,
Svendsen CN and Emson P (2002) Neuronal target genes of the neu-
2011, Woo et al. 2013). According to Woo et al. (2013),
ron‑restrictive silencer factor in neurospheres derived from fetuses with
the down‑regulation of IgSF9b may result in high GA‑ Down’s syndrome: a gene expression study. Lancet 359: 310–315.
BA‑ergic transmission to pyramidal cells resulting in Bajnok A, Ivanova M, Rigó J Jr, Toldi G (2017) The distribution of activation
overall inhibition. However, it is astounding that there markers and selectins on peripheral T lymphocytes in preeclampsia.
is a lack of research on DSCAM and GABA modulation. Mediators Inflamm 2017: 8045161.
Banasr M, Dwyer JM and Duman RS (2011) Cell atrophy and loss in de-
Table IB summarizes changes observed in the levels of
pression: reversal by antidepressant treatment. Curr Opin Cell Biol 23:
DSCAM, Glu, GABA, and modulation of LTP in the dis‑ 730–737.
eases discussed in this review. Barlow GM, Micales B, Chen XN, Lyons GE, Korenberg JR (2002) Mammalian
DSCAMs: roles in the development of the spinal cord, cortex, and cere-
bellum? Biochem Biophys Res Commun 293: 881–891.

CONCLUSIONS Barlow GM, Micales B, Lyons GE, Korenberg JR (2001) Down syndrome
cell adhesion molecule is conserved in mouse and highly expressed in
the adult mouse brain. Cytogenet Cell Genet 94: 155–162.
Over the years, research has shown that upregulation Belichenko PV, Kleschevnikov AM, Becker A, Wagner GE, Lysenko LV, Yu YE,
of DSCAM is involved in cognitive dysregulation and thus Mobley WC (2015) Down syndrome cognitive phenotypes modeled in
is a major cause of mental retardation. However, to date mice trisomic for All HSA 21 homologues. PLoS One 10: e0134861.
Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ, Salehi A,
only a few studies have documented its involvement in
Mobley WC (2004) Synaptic structural abnormalities in the Ts65Dn
mood disorders. Interestingly, DSCAM is regulated by mouse model of Down syndrome. J Comp Neurol 480: 281–298.
the NMDA pathway and is linked to the dysregulation Birch AM, Katsouri L, Sastre M (2014) Modulation of inflammation in trans-
of m‑TOR, resulting in intellectual disability. Although genic models of Alzheimer’s disease. J Neuroinflammation 11: 25.
studies of DSCAM in the context of mood are sparse, the Brenhouse HC, Andersen SL (2011) Nonsteroidal anti‑inflammatory treat-
ment prevents delayed effects of early life stress in rats. Biol Psychiatry
association of the Glu pathway with DSCAM indicates
70: 434–440.
a fruitful and exciting track for future research, as this Chen QS, Kagan BL, Hirakura Y, Xie CW (2012) Impairment of hippocampal
gene/protein seems to be engaged in regulation of den‑ long-term potentiation by Alzheimer amyloid beta-peptides. J Neurosci
drite morphology and synaptic plasticity outside of DS. Res 60: 65–72.
Contestabile A, Magara S, Cancedda L (2017) The GABAergic hypothesis
for cognitive disabilities in Down syndrome. Front Cell Neurosci 11: 54.
Costa AC, Grybko MJ (2005) Deficits in hippocampal CA1 LTP induced by
ACKNOWLEDGEMENTS TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome.
Neurosci Lett 382: 317–322.
This work was supported partially by a grant from Cramer N, Galdzicki Z (2012) From abnormal hippocampal synaptic plas-
the National Science Center UMO‑2014/13/D/NZ7/00292 ticity in down syndrome mouse models to cognitive disability in down
syndrome. Neural Plast 2012: 101542.
(K.S.) and partially by a statutory fund from the Institute
Dan Y, Poo MM (2006) Spike timing‑dependent plasticity: from synapse to
of Pharmacology, PAS, Poland. The author thanks Patryc‑ perception. Physiol Rev 86: 1033–1048.
ja Pańczyszyn‑Trzewik for help in preparing Table I. The Dogliotti G, Galliera E, Licastro F, Corsi MM (2010) Age‑related changes in
author declares that there are no conflicts of interest. plasma levels of BDNF in Down syndrome patients. Immun Ageing 7: 2.
218 K. Stachowicz Acta Neurobiol Exp 2018, 78: 210–219

Doran E, Keator D, Head E, Phelan MJ, Kim R, Totoiu M, Barrio JR, Koch G, Di Lorenzo F, Bonnì S, Ponzo V, Caltagirone C, Martorana A (2012)
Small GW, Potkin SG, Lott IT (2017) Down syndrome, partial trisomy Impaired LTP‑ but not LTD‑like cortical plasticity in Alzheimer’s disease
21, and absence of Alzheimer's disease: the role of APP. J Alzheimers patients. J Alzheimers Dis 31: 593–599.
Dis 56: 459-470. Kossut M (2007) Synaptogenesis in learning and memory (in Polish). (Prze-
Dorostkar MM, Zou C, Blazquez‑Llorca L, Herms J (2015) Analyzing dendrit- włocka B, ed.). Script of XXIV Winter School of IF PAN, 25–30.
ic spine pathology in Alzheimer’s disease: problems and opportunities. Kourtidis A, Lu R, Pence LJ, Anastasiadis PZ (2017) A central role for cadher-
Acta Neuropathol 130: 1–19. in signaling in cancer. Exp Cell Res 358: 78–85.
Duric V, Duman RS (2013) Depression and treatment response: dynamic Kurt MA, Kafa MI, Dierssen M, Davies DC (2004) Deficits of neuronal den-
interplay of signaling pathways and altered neural processes. Cell Mol sity in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in
Life Sci 70: 39–53. a mouse model of Down syndrome. Brain Res 1022: 101–109.
Edelman GM, Crossin KL (1991) Cell adhesion molecules: implications for Li HL, Huang BS, Vishwasrao H, Sutedja N, Chen W, Jin I, Hawkins RD,
a molecular histology. Annu Rev Biochem. 60: 155–190. Bailey CH, Kandel ER (2009) Dscam mediates remodeling of glutamate
Eyre H, Baune BT (2012) Neuroplastic changes in depression: a role for the receptors in Aplysia during de novo and learning-related synapse for-
immune system. Psychoneuroendocrinology 37: 1397–1416. mation. Neuron 61: 527–540.
Ferrer I, Gullotta F (1990) Down’s syndrome and Alzheimer’s disease: den- Li S, Jin M, Koeglsperger T, Shepardson N, Shankar G, and Selkoe D (2011)
dritic spine counts in the hippocampus. Acta Neuropathol 79: 680–685. Soluble A βoligomers inhibit long‑term potentiation through a mecha-
Friedman MJ, Keane TM, Resick PA (2014) Handbook of PTSD. Science and nism involving excessive activation of extrasynaptic NR2B‑containing
Practice. Second Edition, Guilford Press. NMDA receptors. Neuroscience 31: 6627–6638.
Gao J, Wang H, Liu Y, Li YY, Chen C, Liu LM, Wu YM, Li S, Yang C (2014) Gluta- Li Y, Sun H, Chen Z, Xu H, Bu G, and Zheng H (2016) Implications of GAB-
mate and GABA imbalance promotes neuronal apoptosis in hippocam- Aergic neurotransmission in Alzheimer's disease. Front Aging Neurosci
pus after stress. Med Sci Monit 20: 499–512. 8: 31.
St George‑Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Liu W, Ge T, Leng Y, Pan Z, Fan J, Yang W, Cui R (2017) The role of neural
Myers RH, Feldman RG, Pollen D, Drachman D, et al. (1987) The genetic plasticity in depression: From hippocampus to prefrontal cortex. Rev
defect causing familial Alzheimer’s disease maps on chromosome 21. Neural Plasticity 2017: 6871089.
Science 235: 885–890. Lockstone HE, Harris LW, Swatton JE, Wayland MT, Holland AJ, Bahn S
Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285: 1028–1032. (2007) Gene expression profiling in the adult Down syndrome brain.
Grady SE, Marsh TA, Tenhouse A, and Klein K (2017) Ketamine for the treat- Genomics 90: 647–660.
ment of major depressive disorder and bipolar depression: A review of Logue MW, Smith AK, Baldwin C, Wolf EJ, Guffanti G, Ratanatharathorn A,
the literature. Mental Health Clinician 7: 16–23. Stone A, Schichman SA, Humphries D, Binder EB, Arloth J, Menke A,
Gueli MC, Taibi G (2013) Alzheimer’s disease: amino acid levels and brain Uddin M, Wildman D, Galea S, Aiello AE, Koenen KC, Miller MW (2015)
metabolic status. Neurol Sci 34: 1575–1579. An analysis of gene expression in PTSD implicates genes involved in the
Harpaz Y, Chothia C (1994) Many of the immunoglobulin superfamily do- glucocorticoid receptor pathway and neural responses to stress. Psy-
mains in cell adhesion molecules and surface receptors belong to a new choneuroendocrinology 57: 1–13.
structural set which is close to that containing variable domains. J Mol Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress through-
Biol 238: 528–539. out the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci
Hashimoto K, Sawa A, Iyo M (2007) Increased levels of glutamate in brains 10: 434–445.
from patients with mood disorders. Biol Psychiatry 62: 1310–1316. Madder LJC (2017) Aberrant hippocampal morphology and function in
Hattori D, Millard S, Wojtowicz WM, and Zipursky SL (2008) Dscam‑medi- a mouse model for post‑traumatic stress disorder. Nijmegen CNS 12:
ated cell recognition regulates neural circuit formation. Annu Rev Cell 29–82.
Dev Biol 24: 597–620. Martínez‑Cué C, Rueda N, García E, Davisson MT, Schmidt C, Flórez J (2005)
Head E, Lott IT, Patterson D, Doran E, Haier RJ (2007) Possible compensa- Behavioral, cognitive and biochemical responses to different environ-
tory events in adult Down syndrome brain prior to the development mental conditions in male Ts65Dn mice, a model of Down syndrome.
of Alzheimer disease neuropathology: targets for nonpharmacological Behav Brain Res 163: 174–185.
intervention. J Alzheimers Dis 11: 61–76. Mrak RE, Griffin WS (2004) Trisomy 21 and the brain. J Neuropathol Exp
Hebb DO (1949) The organization of behavior: a neuropsychological theo- Neurol 63: 679–685.
ry. Wiley and Sons, New York, USA. Myers BA, Pueschel SM (1991) Psychiatric disorders in persons with Down
Hickey F, Hickey E, Summar KL (2012) Medical update for children with syndrome. J Nerv Ment Dis 179: 609–613.
Down syndrome for the pediatrician and family practitioner. Adv Pedi- Norrholm SD, Ouimet CC (2001) Altered dendritic spine density in animal
atr 59: 137–157. models of depression and in response to antidepressant treatment.
Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, Synapse 42: 151–163.
memory and disease. Trends Neurosci 33: 67–75. Obrietan K, Gao XB, Van Den Pol AN (2002) Excitatory actions of GABA
Hortsch M, Umemori H (2009) The sticky synapse: cell adhesion molecules increase BDNF expression via a MAPK‑CREB‑dependent mechanism –
and their role in synapse formation and maintenance. Springer‑Verlag, a positive feedback circuit in developing neurons. J Neurophysiol 88:
New York. 1005–1015.
Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA, Olson LE, Roper RJ, Baxter LL, Carlson EJ, Epstein CJ, Reeves RH (2004) Down
Karolewicz B (2011) The mTOR signaling pathway in the prefrontal cor- syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit
tex is compromised in major depressive disorder. Prog Neuropsycho- variable severity of cerebellar phenotypes. Dev Dyn 230: 581–589.
pharmacol Biol Psychiatry 35: 1774–1779. Otte C, Lenoci M, Metzler T, Yehuda R, Marmar CR, Neylan TC (2005) Hypo-
Jia YL, Jing LJ, Li JY, Lu JJ, Han R, Wang SY , Peng T, Jia YJ (2011) Expres- thalamic-pituitary-adrenal axis activity and sleep in posttraumatic stress
sion and significance of DSCAM in the cerebral cortex of APP transgenic disorder. Neuropsychopharmacology 30: 1173–1180.
mice. Neurosci Lett 491: 153–157. Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: im-
Jin XK, Li WW, Wu MH, Guo XN, Li S, Yu AQ, Zhu YT, He L, Wang Q (2013) Im- pact on receptor properties, synaptic plasticity and disease. Nat Rev
munoglobulin superfamily protein Dscam exhibited molecular diversity Neurosci 14: 383–400.
by alternative splicing in hemocytes of crustacean, Eriocheir sinensis. Pariante CM, and Lightman SL (2008) The HPA axis in major depression: clas-
Fish Shellfish Immunol 35: 900–909. sical theories and new developments. Trends in Neurosci 31: 464–468.
Acta Neurobiol Exp 2018, 78: 210–219 DSCAM 219

Pennington BF, Moon J, Edgin J, Stedron J and Nadel L (2003) The neuro- Springer TA (1994) Traffic signals for lymphocyte recirculation and leuko-
psychology of Down syndrome: evidence for hippocampal dysfunction. cyte emigration: the multistep paradigm. Cell 76: 301–314.
Child Dev 74: 75–93. Sterne GR, Kim JH, Ye B (2015) Dysregulated Dscam levels act through Abel-
Pérez‑Núñez R, Barraza N, Gonzalez‑Jamett A, Cárdenas AM, Barnier JV, son tyrosine kinase to enlarge presynaptic arbors. eLife 4: e05196.
Caviedes P (2016) Overexpressed Down syndrome cell adhesion mol- Szewczyk B, Pałucha‑Poniewiera A, Poleszak E, Pilc A, Nowak G (2012) In-
ecule (DSCAM) deregulates P21-activated kinase (PAK) activity in an in vestigational NMDA receptor modulators for depression. Expert Opin
vitro neuronal model of Down syndrome: consequences on cell process Investig Drugs 21: 91–102.
formation and extension. Neurotox Res 30: 76–87. Troca‑Marín JA, Alves‑Sampaio A, Montesinos ML (2012) Deregulated
Petty F, Kramer GL, Fulton M, Moeller FG, Rush AJ (1993) Low plasma GABA mTOR‑mediated translration in intellectual disability. Prog Neurobiol
is a trait‑like marker for bipolar illness. Neuropsychopharmacology 9: 96: 268–282.
125–132. Weijerman ME, de Winter JP (2010) Clinical practice. The care of children
Pilc A, Chaki S, Nowak G, Witkin JM (2008) Mood disorders: regulation by with Down syndrome. Eur J Pediatr 169: 1445–1452.
metabotropic glutamate receptors. Biochem Pharmacol 75: 997–1006. Whittle N, Sartori SB, Dierssen M, Lubec G, and Singewald N (2007) Fetal
Pinter JD, Eliez S, Schmitt JE, Capone GT, Reiss AL (2001) Neuroanatomy Down syndrome brains exhibit aberrant levels of neurotransmitters
of Down’s syndrome: a high‑resolution MRI study. Am J Psychiatry 158: critical for normal brain development. Pediatrics 120: 1465–1471.
1659–1665. Wong ChW, Dye DE, Coombe DR (2012) The role of immunoglobulin su-
Pochwat B, Pałucha‑Poniewiera A, Szewczyk B, Pilc A, Nowak G (2014) perfamily cell adhesion molecules in cancer metastasis. Int J Cell Biol
NMDA antagonists under investigation for the treatment of major de- ID: 340296.
pressive disorder. Expert Opin Investig Drugs 23: 1181–1192. Woo J, Kwon SK, Nam J, Choi S, Takahashi H, Krueger D, Park J, Lee Y, Bae JY,
Radley J, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR, McEwen BS, Morrison Lee D, Ko J, Kim H, Kim MH, Bae YC, Chang S, Craig AM, Kim E (2013) The
JH (2004) Chronic behavioral stress induces apical dendritic reorganiza- adhesion protein IgSF9b is coupled to neuroligin 2 via S‑SCAM to pro-
tion in pyramidal neurons of the medial prefrontal cortex. Neuroscience mote inhibitory synapse development. J Cell Biol 201: 929–944.
125: 1–6. Wuwongse S, Cheng SS, Wong GT, Hung CH, Zhang NQ, Ho YS, Law AC,
Rajkowska G, Miguel‑Hidalgo JJ (2007) Gliogenesis and glial pathology in Chang RC (2013) Effects of corticosterone and amyloid‑beta on proteins
depression. CNS Neurol Disord Drug Targets 6: 219–233. essential for synaptic function: Implications for depression and Alzhei-
Saito Y, Oka A, Mizuguchi M, Motonaga K, Mori Y, Becker LE, Arima K, mer’s disease. Biochim Biophys Acta 1832: 2245–2256.
Miyauchi J, Takashima S (2000) The developmental and aging changes Yamagata M and Sanes JR (2010) Synaptic localization and function of Side-
of Down’s syndrome cell adhesion molecule expression in normal and kick recognition molecules require MAGI scaffolding proteins. J Neuro-
Down’s syndrome brains. Acta Neuropathol 100: 654–664. sci 30: 3579–3588.
Sassoè‑Pognetto M, Frola E, Pregno G, Briatore F, and Patrizi A (2011) Un- Yamakawa K, Huot YK, Haendelt MA, Hubert R, Chen XN, Lyons GE,
derstanding the molecular diversity of GABAergic synapses. Front Cell Korenberg JR (1998) DSCAM: a novel member of the immunoglobulin
Neurosci 5: 4. superfamily maps in a Down syndrome region and is involved in the
Schmucker D, and Chen B (2009) Dscam and DSCAM: complex genes in sim- development of the nervous system. Hum Mol Genet 7: 227–237.
ple animals, complex animals yet simple genes. Genes Dev 23: 147–156. Young KA, Thompson PM, Cruz DA, Williamson DE, Selemon LD (2015)
Shyn SI, Shi J, Kraft JB, Potash JB, Knowles JA, Weissman MM, Garriock HA, BA11 FKBP5 expression levels correlate with dendritic spine density in
Yokoyama JS, McGrath PJ, Peters EJ, Scheftner WA, Coryell W, Lawson WB, postmortem PTSD and controls. Neurobiol Stress 2: 67–72.
Jancic D, Gejman PV, Sanders AR, Holmans P, Slager SL, Levinson DF, Yu T, Guo M, Garza J, Rendon S, Sun XL, Zhang W, Lu XY (2011) Cognitive
Hamilton SP (2011) Novel loci for major depression identified by ge- and neural correlates of depression‑like behaviour in socially defeated
nome‑wide association study of Sequenced Treatment Alternatives to mice: an animal model of depression with cognitive dysfunction. Int
Relieve Depression and meta‑analysis of three studies. Mol Psychiatry J Neuropsychopharmacol 14: 303–317.
16: 202–15. Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, Asrar S, Pao A, Chen R, Fan N, Carat-
Siarey RJ, Carlson EJ, Epstein CJ, Balbo A, Rapoport SI, and Galdzicki Z (1999) tini‑Rivera S, Bechard AR, Spring S, Henkelman RM, Stoica G, Matsui SI,
Increased synaptic depression in the Ts65Dn mouse, a model for men- Nowak NJ, Roder JC, Chen C, Bradley A and Yu YE (2010) A mouse model
tal retardation in Down syndrome. Neuropharmacology 38: 1917–1920. of Down syndrome trisomic for all human chromosome 21 syntenic re-
Siarey RJ, Kline‑Burgess A, Cho M, Balbo A, Best TK, Harashima C, Klann E, gions. Hum Mol Genet 19: 2780–2791.
Galdzicki Z (2006) Altered signaling pathways underlying abnormal hip- Zhang Y, Li P, Feng J, Wu M (2016) Dysfunction of NMDA receptors in Alzhei-
pocampal synaptic plasticity in the Ts65Dn mouse model of Down syn- mer’s disease. Neurol Sci 37: 1039–1047.
drome. J Neurochem 98: 1266–1277. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ (2013) Ketamine‑induced
Sibley DR, Hanin I, Kuhar M, Skolnik P (2007) Handbook of contemporary antidepressant effects are associated with AMPA receptors‑mediated
neuropharmacology. Vol 1, Wiley and Sons, Hoboken. upregulation of mTOR and BDNF in rat hippocampus and prefrontal
Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, cortex. Eur Psychiatry 29: 419–423.
Del‑Favero J, Cruts M, van Duijn CM, Van Broeckhoven C (2006) APP Zhu H, Hummel T, Clemens JC, Berdnik D, Zipursky SL, Luo L (2006) Den-
duplication is sufficient to cause early onset Alzheimer’s dementia with dritic patterning by Dscam and synaptic partner matching in the Dro-
cerebral amyloid angiopathy. Brain 129: 2977–2983. sophila antennal lobe. Nat Neurosci 9: 349–355.