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Prog Neuropsychopharmacol Biol Psychiatry. Author manuscript; available in PMC 2019
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March 02.
Published in final edited form as:
Prog Neuropsychopharmacol Biol Psychiatry. 2018 March 02; 82: 187–194. doi:10.1016/j.pnpbp.
2017.11.016.
PSD95: a synaptic protein implicated in schizophrenia or
autism?
Austin A. Coley and Wen-Jun Gao*
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia,
PA 19129
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Abstract
The molecular components of the postsynaptic density (PSD) in excitatory synapses of the brain
are currently being investigated as one of the major etiologies of neurodevelopmental disorders
such as schizophrenia (SCZ) and autism. Postsynaptic density protein-95 (PSD-95) is a major
regulator of synaptic maturation by interacting, stabilizing and trafficking N-methyl-D-aspartic
acid receptors (NMDARs) and α-amino-3-hydroxy-5- methyl-4-isox-azoleproprionic acid
receptors (AMPARs) to the postsynaptic membrane. Recently, there has been overwhelming
evidence that associates PSD-95 disruption with cognitive and learning deficits observed in SCZ
and autism. For instance, recent genomic and sequencing studies of psychiatric patients highlight
the aberrations at the PSD of glutamatergic synapses that include PSD-95 dysfunction. In animal
studies, PSD-95 deficiency shows alterations in NMDA and AMPA-receptor composition and
function in specific brain regions that may contribute to phenotypes observed in neuropsychiatric
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pathologies. In this review, we describe the role of PSD-95 as an essential scaffolding protein
during synaptogenesis and neurodevelopment. More specifically, we discuss its interactions with
NMDA receptor subunits that potentially affect glutamate transmission, and the formation of silent
synapses during critical time points of neurodevelopment. Furthermore, we describe how PSD-95
may alter dendritic spine morphologies, thus regulating synaptic function that influences
behavioral phenotypes in SCZ versus autism. Understanding the role of PSD-95 in the
neuropathologies of SCZ and autism will give an insight of the cellular and molecular attributes in
the disorders, thus providing treatment options in patients affected.
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*
Corresponding Author: Wen-Jun Gao, Ph.D., Department of Neurobiology and Anatomy, Drexel University College of Medicine,
2900 Queen Lane, Room 243, Philadelphia, PA 19129, Phone: (215) 991-8907, Fax: (215) 843-9082, wg38@drexel.edu.
Disclosure of Conflicts of Interest
The authors report no biomedical financial interests or potential conflicts of interest.
Ethical Statement
The authors have read and have abided by the statement of ethical standards for manuscripts submitted to the Progress in
Neuropsychopharmacology & Biological Psychiatry. We declare that submitted manuscript does not contain previously published
materials and are not under consideration for publication elsewhere. Each author has made a significant scientific contribution to the
study, and is familiar with the literature reviewed. All authors have read the manuscript and have approved submission of the paper.
The manuscript is original work without fabrication, fraud, or plagiarism. All authors declare no conflicts of interest.
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Keywords
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Neurodevelopment; glutamate; PSD-95; NMDAR; AMPAR; schizophrenia; autism

Introduction
Synaptic dysregulation of dendritic spines during neurodevelopment is becoming
increasingly linked to neurological diseases. Schizophrenia (SCZ) and autism are highly
prevalent disorders characterized by synaptic abnormalities that lead to social impairments
and cognitive deficits in individuals (Hutsler and Zhang, 2010, Selemon and Goldman-
Rakic, 1999). The on-set and symptomology of these maladies are currently being explored
at the dendritic spines to gain a better understanding of the effects and potential treatment
options. SCZ is a heterogeneous mental health disorder that affects 1.1% of the human
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population. Typically, the on-set of SCZ occurs during the adolescent age range and consists
of positive, negative and cognitive symptoms. Positive and negative symptoms involve
hallucinations/delusions and emotional blunting, respectively. The cognitive dysfunctions
include impaired working memory, lack of executive functions and attention deficits. In
contrast, autism is a neurodevelopmental disorder that affects on average 1 in 68 of the
childhood population and is considered within the autism spectrum disorder (ASD) (Toro et
al., 2010). Autistic patients experience symptoms that include behavioral abnormalities such
as repetition, reduced vocal communication, and aberrant social interactions. The prevailing
theories of SCZ and autism etiologies suggest that a disruption of the synapse during
neurodevelopment will cause impairments in synaptic plasticity and synaptic processing that
are characteristic of these disorders.

The postsynaptic density (PSD) is a dense localized area within dendritic spines of
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excitatory synapses and is comprised of receptors, kinases, structural proteins and signaling
molecules associated with synaptic plasticity. Perhaps the most abundant protein of the PSD
is postsynaptic density protein-95 (PSD-95) (Cheng, 2006, Cho et al., 1992), a member of
the membrane-associated guanylate kinase family (MAGUK), a scaffolding protein located
at excitatory synapses and is involved in the stabilization, recruitment and trafficking of N-
methyl-D-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4- isox-
azoleproprionic acid receptors (AMPARs) to the postsynaptic membrane (Chen et al., 2000,
Kornau et al., 1995). PSD-95 is an essential component involved in glutamatergic
transmission, synaptic plasticity, and dendritic spine morphogenesis during
neurodevelopment (Funke et al., 2005, Gilman et al., 2011, Kim, 2004). Therefore, it is
plausible that PSD-95 dysfunction during development may alter synaptic plastic events at
the dendritic spines that contribute to the malformations of the synapse-associated with
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neurological disorders.

There is overwhelming evidence from human and animal studies that suggest PSD-95
disruption is linked to the neuropathologies of SCZ and autism. Specifically, a variety of
sequencing techniques and analytics were used to identify PSD-95 mutations in SCZ and
autism patients (Table 1). For instance, exome sequencing studies of SCZ patients show
disrupted mutations of proteins located in the excitatory synapses of the PSD such as

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NMDAR and PSD-95 (Fromer, 2014, Purcell and Duncan, 2014). Further evidence reveals a
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significant decrease in PSD-95 mRNA and protein expression levels in the dorsolateral and
dorsomedial prefrontal cortex of schizophrenic postmortem patients (Catts, 2015),
suggesting an association between PSD-95 dysfunction and SCZ. PSD-95 has also been
shown to be involved in a network of interactions with high-risk ASD genes that include
SHANK, HOMER, neuroligin, and FMR1 (De Rubeis et al., 2014, Gilman, Iossifov, 2011,
Tsai, 2012). Additionally, in mouse studies, deletion of the DLG4 gene (encodes PSD-95)
causes behavioral abnormalities such as an increase in repetitive behavior, decreased
vocalization, and irregular social interactions consistent with phenotypes observed in ASD
patients (Feyder, 2010). “Furthermore, in a recent genetic study, DLG4 was identified as a
candidate gene disrupted in intellectual disability (ID) (Lelieveld et al., 2016) (Table 1), a
cognitive and mental disorder characterized by a reduction of dendritic spines. Interestingly,
PSD-95 has direct interactions with ID-related proteins within the excitatory PSD that
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include Arc and Interleukin-1-receptor accessory protein-like 1 (IL1RAPL1), responsible for

regulating spine density and function (Fernández et al., 2017, Pavlowsky et al., 2010,
Valnegri, 2011). Therefore, PSD-95 deficiencies could attribute to the loss of spines and
cognitive impairments associated with the ID. In this review, we provide an in-depth
discussion of the role of PSD-95 in glutamatergic transmission and speculate on its
implications in SCZ and autism. Moreover, we outline evidence that illustrates the effects of
PSD-95 dysfunction and NMDAR regulation that include the formation of silent synapses.
Lastly, we propose potential treatment options that restore PSD-95 within dendritic spines as
a therapeutic option for SCZ and autism.

PSD-95: a major component of the neurodevelopment of excitatory

synapses
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PSD-95 (also known as SAP90, synapse-associated protein 90) is encoded by the DLG4
(discs large homolog 4) gene in humans and is a major member of the MAGUK family. It
functions as a scaffolding protein at excitatory synapses of the PSD. PSD-95 consists of
three N-terminal PDZ domains (PSD-95, dlg, and zonula occludens-1), src homology
domain (SH3), and a catalytically inactive guanylate cyclase domain (GUK) (Cho, Hunt,
1992, Kim, 2004). PSD-95 binds via PDZ domains directly to carboxy-terminal tails of
NMDA receptor subunits, NR2A and NR2B, and to the AMPA receptor accessory proteins
through stargazin/TARPs (Zhang, 2013) (Figure 1). Moreover, PSD-95 is a major
component of a large network of proteins within PSD including ion channels, receptors,
adhesion proteins, scaffolding proteins, and signaling molecules that influence glutamatergic
transmission. For instance, PSD-95 has direct interactions with K+ channels, neuroligin, and
nNOS; and indirect interactions with mGluR1/5 via GKAP (Brenman et al., 1996, Irie et al.,
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1997, Kim et al., 1997, Kim and Niethammer, 1995) (Table 2). Additional members of the
MAGUK family include SAP102, SAP97, and PSD-93: and are also responsible for the
recruitment and stabilization of NMDA and AMPA receptors.

PSD-95 has long been associated with synaptic plasticity of glutamatergic synapses during
neurodevelopment due to its interaction and functional implications of NMDA and AMPA
receptors. Synaptic plastic processes such as long-term potentiation (LTP) and long-term

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depression (LTD) are heavily involved in synaptic maturation of the dendritic spine;
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therefore, alterations of the PSD may compromise the integral process of spine formation
leading to neuropathologies of the synapse. Thus, PSD-95 may act as a key component
involved in regulating synaptic strength by controlling spine formation and/or spine
elimination/pruning.

PSD-95 mediates NMDA receptor clustering and function

The PSD site for excitatory glutamatergic transmission is mainly composed of glutamatergic
receptors, including both NMDA and AMPA receptors. NMDA receptors are essential for
synaptic plasticity and cortical development, and functional processes such as learning and
working memory (Collingridge, 2013, Dumas, 2005). NMDA receptors consist of a hetero-
tetrameric complex that contains an obligatory homodimer of NR1 and homodimers or
heterodimers of either NR2A-D or NR3A-D subunits. NR2-containing subunits are involved
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in mediating calcium (Ca+) influx at the postsynaptic membrane; however, the open
probability and duration of Ca+ flux are subunit specific. For instance, NR2B-containing
NMDA receptors have slower kinetics and a slower decay time compared to NR2A-
containing NMDA receptors, thus resulting in a larger flow of Ca+ within the synapse.
PSD-95 influences NMDA receptor transmission via direct interaction and stabilization of
specific NR2-containing NMDA receptors to the postsynaptic membrane. PSD-95 RNAi
knockdown increases NR2B clustering at the postsynaptic synapse in cultured hippocampal
neurons (Bustos, 2014). Additionally, in the hippocampus of a PSD-95 knockout mouse
model, a reported increase in NMDAR decay was shown, suggesting a high presence of
NR2B-containing NMDA receptors, thus corroborating previous findings (Beique, 2006).
NR2B is essential for synaptic maturation during development (Monaco et al., 2015) and
cognitive processes within the adult (Wang et al., 2013). However, an overabundance may be
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hazardous due to the significant increase in Ca+ conductance that could lead to
excitotoxicity and neuronal death (Hardingham, 2006, Monaco, Gulchina, 2015). Therefore,
a downregulation of PSD-95 may subsequently result in a substantial increase in Ca+ influx.
Ca+ excitotoxicity within specific areas may impair tissue function, leading to
neuropathologies depending on the brain region.

PSD-95: a regulator of NMDA receptor development

Glutamatergic receptor composition varies at the PSD of excitatory synapses during
neurodevelopment. For instance, PSD scaffolding proteins – PSD-95 and SAP102 – are
involved in NMDA receptor subunit localization and stabilization at the postsynaptic
membrane that indeed facilitates the maturation of the PSD. Within the brain, PSD-95
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expression levels show an increase from early life to adulthood and become more stable
within the adult animal (Glantz, 2007, Gray, 2006), in contrast with SAP102 expression
levels decreasing with age. Concomitantly, there is an NR2B-to NR2A-subunit switch that
occurs during early development in most brain regions, facilitating synaptic maturation
(Dumas, 2005). NR2B protein expression levels are highly abundant during early
development and decline into adulthood; however, NR2A levels begin low but soon rise to
peak along the maturation of associate learning. This would suggest that SAP102/NR2B-
NMDAR complexes are switched by PSD-95/NR2A-NMDAR complexes during

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neurodevelopment, further corroborating PSD-95 as a molecular mediator of NMDA

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receptor development within the PSD. However, the development of prefrontal cortex is
known to be protracted until young adult. Physiologically, NR2B-containing NMDA
receptors also play a dominant role in synaptic plasticity within the adult prefrontal cortex,
responsible for working memory function and cognitive performances (Monaco, Gulchina,
2015, Wang, 2008). NR2B receptors conduct a large amount of Ca+ and Na+ due to the
prolonged open channel state, thereby prolonging depolarization. An overabundance of
NR2B at the synapse is thus becoming a risk factor for excitatory synapses during the
delayed prefrontal cortical development (Monaco, Gulchina, 2015). Therefore, a PSD-95/
SAP102 expression level, as well as an NR2B/NR2A composition at the postsynaptic
membrane during development, is extremely critical for normal synaptic maturation,
especially for the prefrontal cortex. Thus, a disruption of PSD-95 within the PSD may lead
to abnormal glutamatergic transmission due to a shift in NMDA receptor subunits and
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properties. For instance, a reduction in PSD-95 expression will result in a dramatic increase
in NR2B-containing NMDAR presence that may induce hyperexcitability at the synapses,
leading to cell death or neuronal damage.

PSD-95 modulates synaptic plasticity via AMPA receptors

AMPA receptors, composed of GluR1-GluR4 subunits, are heavily involved in
synaptogenesis and essential for mediating synaptic strength. PSD-95 binds directly to
stargazin/TARPs, responsible for interacting with AMPA receptor subunit, GluR1 (Schnell,
2002); and thus is shown to be a key regulator of synaptic plasticity and glutamatergic
transmission (Bustos, 2014). Corroborating evidence describes that there is a significant
reduction of AMPAR-mediated current and GluR1 protein expression levels in the
hippocampus of PSD-95−/− mice (Beique, 2006), suggesting that a downregulation of
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PSD-95 leads to synaptic depression. Furthermore, overexpressing PSD-95 causes an

increase in AMPA-receptor presence and an increase in dendritic spine number and density,
thereby inducing synaptogenesis (El-Husseini et al., 2000). These results suggest that
PSD-95 acts as a regulator of synaptic plastic processes such as LTP and/or LTD via AMPA
receptor scaffolding; thus determining the dendritic spine size, shape and number for
synaptic transmission. Anomalous spine formation and elimination during
neurodevelopment are associated with neuropsychiatric disorders; for instance,
schizophrenic patients display a reduction of spine numbers, in contrast to autism patients
that exhibit an increase in spines (Penzes et al., 2011).

Another major finding is PSD-95 downregulation leads to “silent synapse” formation

(Beique, 2006, Huang, 2015). Silent synapses, also described as immature synapses, can be
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characterized by a high abundance of NMDA receptors and an absence of AMPA receptors

at the postsynaptic membrane, thereby attenuating glutamatergic transmission. The lack of
AMPA receptors at the synapse is mainly attributed to a reduction of PSD-95; however, there
is also an increase in NR2B clustering. If PSD-95 is involved in recruiting NMDA receptors,
then how will a lack of PSD-95 cause an upregulation in NR2B-NMDA containing
receptors? Investigators proposed a compensatory increase of SAP-102 and PSD-93
expression levels to explain this phenomenon. Triple knockdown studies of PSD-95/
SAP-102/PSD-93 show an attenuation of NMDAR-mediated current, in corroborating with

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this theory (Chen, 2015); but how exactly each of the three proteins contributes to the
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alteration of NMDA receptor subunits in the synapses remains to be determined.

Nonetheless, PSD-95 deficiency alone leads to silent synapse formation and could be
associated with the neuropathologies observed in psychiatric disorders.

PSD-95: genetic implications in SCZ

SCZ is a chronic mental disorder that manifests in adolescence or early adulthood due to
changes in molecular and biochemical events that occur during development (Cash-Padgett
and Jaaro-Peled, 2013). Patients display an array of clinical symptoms that consist of
positive symptoms, negative symptoms, and cognitive impairments that include
hallucinations/delusions, emotional blunting, and lack of executive function, respectively.
Environmental and genetic factors during development, such as infection, drug use, parental
age, prenatal and early postnatal or childhood stress have all been linked to the development
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of SCZ. Most genes identified as affected by these factors and dysregulated in SCZ are
involved in neurodevelopment, neuronal growth and migration. Investigators have identified
multiple high-risk genes and protein complexes associated with NMDA dysfunction and
SCZ (i.e., neuregulin, dysbindin, and neuroligin) (Schizophrenia Working Group of the
Psychiatric Genomics, 2014, Soares et al., 2011). Recently, exome sequencing studies of
SCZ patients show disrupted mutations of proteins located at excitatory synapses of the PSD
that include PSD-95, SAP-102 and NMDA receptors (Fromer, 2014, Purcell and Duncan,
2014). Therefore, an anomalous interaction between PSD-95 and NMDA receptors could be
responsible for the maladaptive changes observed in SCZ during neurodevelopment. For
instance, PSD-95 responsible for the stabilization of NMDAR’s at the postsynaptic
membrane may be severely compromised, thus, contributing to a malformed PSD and
glutamatergic dysfunction. Interestingly, PSD-95 binds directly to high-risk SCZ proteins
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such as DISC1 and neuroligin, responsible for synapse formation, microtubule network
dynamics, axonal elongation, and cell adhesion; respectively (Shinoda, 2007, Taya, 2007).
Therefore, disruption of PSD-95 expression/function may influence protein complexes
involved in maladaptive synapse formation leading to schizophrenic- like phenotypes.

PSD-95 & NMDAR dysregulation in SCZ

NMDA receptor hypofunction is highly associated with the pathophysiology of SCZ (Lau
and Zukin, 2007, Snyder et al., 2013). Studies reveal disruptive mutations of NMDA
receptor subunits in the prefrontal cortex, hippocampus, and thalamus in postmortem
subjects with SCZ (Clinton et al., 2003, Kristiansen et al., 2006). Additionally, functional
imaging studies show reduced activity in the dorsolateral prefrontal cortex (dlPFC) in
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patients. More specifically, single photon emission computed tomography (SPECT) display
“hypofrontality” in SCZ patients (Amen et al., 2011). Furthermore, genetic studies report
single-nucleotide polymorphisms (SNPs) and a reduction of NR1 protein and mRNA in the
dorsolateral prefrontal cortex in postmortem subjects (Clinton, Haroutunian, 2003, Weickert
et al., 2013), suggesting a decrease in translation and lack of NMDA receptor presence at the
postsynaptic membrane. Accordingly, schizophrenic patients display a reduction in PSD-95
mRNA and protein expression levels in the dorsolateral and dorsomedial prefrontal cortex
(Catts, 2015). This data localized PSD-95 downregulation in specific forebrain tissue that

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may attribute to cellular phenotypes as well as schizophrenic patient symptomology.

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Hypothetically, a downregulation of PSD-95 may cause an overall reduction in NMDA

receptors presence and function at the postsynaptic membrane. However, evidence within
the hippocampus shows that PSD-95 deficiency exhibits no changes in NMDAR receptor
amplitude, and is likely attributed to compensation via SAP-102 and PSD-93 (Elias, 2006).
Nevertheless, PSD-95 disruption may shift the balance of responsibilities, thus altering
tissue function that contributes to abnormal behavior within psychiatric patients.

PSD-95 regulates spine density involved in SCZ

Normal synaptic formation during neurodevelopment is critical for proper synaptic function;
therefore, key components within the PSD, such as PSD-95, and SHANK help regulate
synaptic growth and sustain molecular organization at the synapse. More specifically, within
the prefrontal cortex, PSD-95 plays an essential role in postsynaptic development and
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function. During development, PSD-95 protein expression levels increase until late
adolescence and early adulthood, consistent with synaptic density growth in the human
prefrontal cortex (Glantz, 2007). However, PSD-95 is highly susceptible in schizophrenic
patients; and thus, may alter normal spine growth and synaptic physiology. Neuroanatomical
evidence of SCZ patients shows structural aberrations in specific tissues; for instance, an
overall decrease in brain volume and reduced cortical gray matter in forebrain tissue, such as
the dorsolateral prefrontal cortex, superior temporal gyrus, and limbic areas (i.e.,
hippocampal formation, anterior cingulate cortex) were reported in SCZ patients. At the
cellular level, reports show a reduction in neuronal number and dendritic spine densities in
the hippocampus and dorsolateral prefrontal cortex (Glantz and Lewis, 2000, Kolluri et al.,
2005), although this observation appears to be controversial. However, many studies
corroborate a significant decrease in pyramidal dendritic spines within superficial layers of
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the prefrontal cortex (Glantz and Lewis, 2000, Selemon and Goldman-Rakic, 1999), which
is due to a spine-turnover rate during development. For example, in normal human subjects,
spine numbers increase prior to birth and into childhood, spines are then selectively
eliminated during adolescence. Therefore, we presume that within SCZ patients, there is an
increase in spine number elimination (due to exaggerated spine pruning) that occurs during
adolescence, contributing to the emergence of schizophrenic- like symptoms (Figure 2A).

In fact, the molecular mechanisms involved that promote synaptic elimination in SCZ
patients remains elusive. We propose that a reduction in dendritic spine numbers within SCZ
patients is attributed to a deficient and/or dysfunctional PSD-95 scaffolding protein at the
synapse (Figure 2B). Specifically, PSD-95 regulates dendritic spine numbers via synaptic
plastic process through its interactions with NMDA- and AMPA-receptors. We suggest that
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when PSD-95 is disrupted, it will cause a decrease in the stabilization of NMDAR receptors
— more specifically, NR2A-containing receptors — at the postsynaptic membrane, causing
an attenuation of NMDAR signaling and a loss of spines. Moreover, fewer AMPA receptors
will be recruited to the PSD during spine formation, thus severely inhibiting spinogenesis.
Nevertheless, PSD-95 deficiency leads to silent synapse formation due to an increase in the
NMDAR/AMPAR ratio at the synapse (Beique, 2006, Huang, 2015), and thus has been
previously theorized to lead to synaptic elimination (Hanse, 2013). In addition, it is reported
that a disruption in ErbB4 signaling, which is highly associated to SCZ, causes a

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destabilization of AMPA-receptors and loss of NMDA-receptors at the postsynaptic

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membrane (Li, 2007). Since PSD-95-ErB4 interactions are critical for ErB4 signaling
(Barros CS, 2009), we suggest that a PSD-95 mutation would severely diminish the
signaling pathway responsible for synaptic growth, consequently causing spine loss. Indeed,
an altered neuregulin-1-ErB4 signaling contributes to NMDAR hypofunction observed in
postmortem brains of SCZ patients (Hahn, 2006). We presume it is plausible that a reduction
in PSD-95 within the frontal cortices of patients with schizophrenia will lead to a dramatic
loss in dendritic spines, thus inducing schizophrenic- like symptoms that include cognitive
deficits and working memory impairments. Consistently, a reduction in spine numbers will
lead to glutamatergic attenuation and hypofrontality within the brain; thus, the overall
reduction in neuronal activity in the dlPFC could explain the cognitive deficits and negative
symptoms exhibited in patients with SCZ.
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PSD-95: genetic implications in autism

Autism is a neurodevelopmental disorder characterized by behavioral abnormalities such as
repetition, reduced vocal communication, and aberrant social interactions; therefore, can be
described as a disorder of the synapse. Genomic screenings of autism patients display
genetic mutations of synaptic proteins that include PSD-95 (Mariner et al., 1986, Risch et
al., 1999). More recently, exome sequencing studies reveal PSD-95 as a high-risk gene
involved in autism-spectrum disorders (De Rubeis, He, 2014). Furthermore, network-based
analysis of genetic associations (NETBAG) identifies gene clusters such as dlg4, affected by
de novo CNV events in autistic individuals (Gilman, Iossifov, 2011). In behavioral studies,
PSD-95 knock-out mice exhibit similar phenotypes, consistent with autism spectrum
disorders such as repetitive behavior (increased grooming) and decreased vocalization
(Feyder, 2010). These studies suggest PSD-95 gene disruption may be associated with
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autism-related phenotypes observed in autistic patients. However, how a reduced PSD-95

expression in the brain results in an opposite change in dendritic spine, i.e., decrease in SCZ
and increase in autism, remains an unsolved dilemma.

PSD-95: interaction with high-risk autism-related proteins

A large network of macromolecules present at the PSD has been implicated in autism,
including SHANK, homer, FMRP (fragile x mental retardation protein), and neuroligin;
interestingly, these molecules are described to have either direct or indirect interaction with
PSD-95 that may alter synaptic structure and activity (Fujita-Jimbo et al., 2015, State, 2010,
Tsai, 2012, Xing, Kimura, 2016). For example, PSD-95 is heavily involved in recruiting the
cell adhesive molecule neuroligin to excitatory synapses during neurodevelopment. A
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PSD-95-neuroligin complex is critical for promoting neuronal connections between cells

and inducing synaptic maturation (Prange et al., 2004); therefore, an overabundance of this
complex could disrupt normal synaptic formation. PSD-95 is also associated with fragile X
syndrome via FMRP mutations, consequently leading to a reduction in PSD-95 proteosomal
degradation and a decrease in synaptic elimination (Todd et al., 2003, Zalfa et al., 2007).
These findings illustrate that high-risk autism-related proteins may alter synaptic formation
by regulating PSD-95 ubiquitination, synthesis, and location within the PSD.

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PSD-95: alters spine density involved in autism

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A major cellular phenotype identified in autism patients is dendritic spine aberrations; for
instance, in humans, there is an increase in spine density on apical dendrites of pyramidal
neurons in layer 2/3 of frontal, parietal, and temporal lobes. During development in normal
subjects, spine pruning occurs as a part of synaptic maturation. However, in the autistic
brain, dendritic spines undergo less pruning/elimination, and exhibit rapid growth and
formation that occur during childhood (Figure 3A). For example, in the fragile X autism
brain, there are increases in spine density that are associated with aberrant synaptic
connectivity and plasticity (Irwin et al., 2001). Furthermore, autism is characterized by
hyperconnectivity in local circuitry, although observations of hypoconnectivity are seen
between brain regions (Penzes, Cahill, 2011). The hyperconnectivity is mainly attributed to
an increase in spine density at the dendritic spines; thus, altering synaptic transmission
leading to social deficits and cognitive impairments seen in patients.
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Scaffold proteins, such as SHANK and homer are heavily involved in anomalous maturation
of the synapse; however, PSD-95 may also play a role. Indeed, previous studies show that
PSD-95 overexpression causes an increase in AMPA-receptor presence and activity, and is
accompanied with an increase in spine size and density in cultured hippocampal neurons
(El-Husseini, Schnell, 2000). More specifically, PSD-95 overexpression induces LTP via
recruitment of GluR1-containing AMPA receptors to synaptic membranes (Ehrlich, 2004).
This finding suggests that an aberrant increase in spine density is consequently due to
PSD-95 overabundance.

We propose hypothetical models that highlight the involvement of PSD-95 and dendritic
spine growth (Figure 3B). Previous reports show FMRP dysregulation strongly influences
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the presence and function of PSD-95. For instance, in FMR1 knock-outs, a model for fragile
x syndrome, there is an increase in total protein levels of PSD-95 that is consistent with
increases in GluR1 protein levels at the synapse (Muddashetty et al., 2007, Todd, Mack,
2003). Indeed, FMRP was eloquently described as a major mediator in synaptic translation
of receptors, kinases, scaffolding proteins via eukaryotic elongation factor 4F (eIF4F)
(Richter, 2015). For example, FMRP dephosphorylation causes an increase in PSD-95
translation via mGluR1 dependent mediated pathways (Muddashetty, 2011, Nalavadi, 2012).
It was further illustrated that PSD-95 ubiquitination is suppressed in the absence of FMRP,
thus contributing to a reduction in synaptic elimination and subsequent enhanced synaptic
formation (Tsai, 2012). These studies reveal that deactivation or loss of FMRP causes an
increase in PSD-95 protein expression at the synapse and a dramatic increase in the
recruitment of AMPA-receptors to the postsynaptic membrane. Therefore, we suggest that a
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disruption of FMRP utilizes PSD-95 scaffolding machinery to induce abnormal dendritic

spine formation within the cortical tissue of autism patients.

Conclusions and future perspectives

The dendritic spine is the site of the PSD of excitatory synapses and is tightly regulated by
synaptic proteins that influence glutamatergic transmission. However, within neurological
disorders, there is a disruption of proteins within a PSD network that leads to the

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pathogenesis of SCZ and autism. Among these proteins, PSD-95 is involved in the
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recruitment and stabilization of glutamate receptors and is a major regulator of the

maturation of glutamatergic synapses. An imbalance of PSD-95 expression will alter AMPA
receptor composition and function, as well as NMDAR stabilization and kinetics, thus
modifying glutamatergic transmission. PSD-95 also influences the size and density of
dendritic spines during neurodevelopment that has overwhelming effects on synaptic
connectivity and activity.

A major question remains, how is PSD-95 implicated in both SCZ and autism? For instance,
sequencing studies show that PSD-95 gene mutations are associated with both SCZ and
autism (Xing, Kimura, 2016). A plausible hypothesis would be that PSD-95 deficiency is
associated with SCZ, whereas an overabundance of PSD-95 is linked to autism. However,
this intriguing hypothesis remains to be tested. One way to investigate this theory is to
establish a PSD-95 mutant animal model to assess the behavioral correlations with patients
Author Manuscript

that exhibit psychiatric symptoms. Determining the behavioral effects of PSD-95 deficiency
or overexpression and its association with SCZ and/or autism symptomology will provide
greater insights from clinical aspects. Further, understanding the neuroanatomical and
physiological effects of PSD-95 mutations can be used to compare to the established
schizophrenic and autistic animal models such as neuregulin and SHANK3, respectively.
These studies are important in understanding PSD-95 as a major regulator during
neurodevelopment and synaptic transmission and associate these findings to
neuropsychiatric disorders.

Acknowledgments
The authors acknowledge Erin McEachern for reading and commenting on the manuscript. This work is provided
by the NIH R01MH085666 and NARSAD Independent Investigator Award 2015 to W.J. Gao.
Author Manuscript

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Highlights
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• PSD-95 mediates NMDA and AMPA receptor clustering and function

• Genetic implications of PSD-95 deficiency in schizophrenia

• PSD-95 & NMDAR dysregulation in schizophrenia

• PSD-95 regulates spine density involved in schizophrenia

• PSD-95 is associated with NMDAR dysregulation and spine change in autism

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Figure 1.
PSD-95 interactions in the PSD. An illustration describing the molecular organization of the
postsynaptic density (PSD) located in the dendritic spine of glutamatergic synapses.
Postsynaptic density-95 (PSD-95) contains direct and indirect interactions with many
macromolecules at the PSD. PDZ1 domains of PSD-95 bind directly to N-methyl-D-aspartic
acid receptors (NMDARs), more specifically, NR2-containing NMDA-receptors. PSD-95
also interacts with ErbB4, neuroligin, and nNos. PSD-95 has indirect interactions with α-
amino-3-hydroxy-5-methyl-4- isox-azoleproprionic acid receptors (AMPARs) via stargazin.
Other indirect interactions include group 1/5 mGluRs via GKAP, shank, and homer; and
actin polymers via GKAP and cortactin. nNos, Neuronal nitric oxide synthase; GKAP,
guanylate kinase-associated protein; mGluR, metabotropic glutamate receptors.
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Figure 2.
Dendritic spine changes in schizophrenia. (A) Graph showing dendritic spine development
in patients with schizophrenia (yellow) versus normal brains (black). (B) Hypothetical
models for the decrease in number of dendritic spines in SCZ patients. PSD-95 mutations
disrupt ErbB4-neuregulin signaling causing AMPAR’s to destabilize from the postsynaptic
membrane and a loss of NMDAR’s. However, enhanced neuregulin-Erb4 signaling leads to
NMDAR hypofunction and loss of spines. A disrupted or deficient amount of PSD-95
results in a loss of NMDAR’s (NR2A-containing) and AMPAR receptors present at the
membrane.
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Figure 3.
Dendritic spine changes in autism. (A) Graph showing dendritic spine development in
autism patients (orange) versus normal brains (black). (B) Hypothetical models for the
increase in number of dendritic spines within autism patients. The absence of FMRP causes
a reduction in PSD-95 degradation and subsequent increase in AMPAR recruitment to the
postsynaptic membrane. FMPR dephosphorylation causes an increase in PSD-95 translation
via group 1 mGluR activation, thus increasing AMPAR recruitment to the postsynaptic
membrane.
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Table 1

Mutations identified in the DLG4 gene in schizophrenia, autism and intellectual disability.
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Mutation Disorder Methods Reference

DLG4; Singleton Schizophrenia Exome sequence analysis (Purcell and Duncan, 2014)

DLG4; de novo copy number variation (CNV) Autism NETBAG analysis (Gilman et al., 2011)

DLG4-G241S Autism Ion PGM platform sequencing (Xing et al., 2016)

DLG4; de novo Autism smMIP screening (Stessman et al., 2017)

DLG4; de novo Intellectual disorder Meta- analysis (Lelieveld et al., 2016)

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Table 2

PSD-95 interacting protein network.

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Interacting protein Interacting domain Reference

NMDA receptor subunit NR2 PDZ domains (1-2) (Kornau et al., 1995)

Stargazin (Interacts with AMPA receptor subunits GluR1, GluR2, and PDZ domain (1) (Chen et al., 2000)
GluR4)

K+ channel PDZ domains (1-2) (Kim and Niethammer, 1995)

Neuroligin PDZ domain (3) (Irie et al., 1997)

GKAP (Interacts with mGluR1/5 via SHANK-Homer; and F-actin via GK domain (Kim et al., 1997)
SHANK)

nNos PDZ domain (2) (Brenman et al., 1996)

ErB4 PDZ domains (1-2) (Garcia et al., 2000)

SPAR GK (Pak and Sheng, 2003)

Kalirin PDZ domains (1-3) (Penzes et al., 2001)

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SynGAP PDZ domains (1-3) (Kim et al., 1998)

AKAP SH3 and GK domains (Colledge, 2000)

Src family: Src, lyn and Yes PDZ domains (1-3) and SH3 domain (Kalia and Salter, 2003)

IRSp53 PDZ domain (2) (Soltau, 2004)

CRIPT PDZ domain (3) (Passafaro et al., 1999)

Arc PDZ domains (1-2) (Fernández et al., 2017)

IL1RAPL1 PDZ domains (1-2) (Pavlowsky et al., 2010)
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Prog Neuropsychopharmacol Biol Psychiatry. Author manuscript; available in PMC 2019 March 02.