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Molecular and synaptic defects in intellectual disabilitysyndromesChiara Verpelli1,2 and Carlo Sala1,2

The search for genetic causes of intellectual disability has

identified, over the past twenty years, numerous mutated

genes that code for proteins concerned with synapse function.

Functional studies have shown that these genes may be

involved in synapse formation, the synthesis and degradation

of specific synapse proteins, the regulation of dendritic spine

morphology, or regulation of the synaptic cytoskeleton. It is

now clear that even mild alterations in synapse morphology and

function can give rise to intellectual disability, and

pharmacological agents able to counteract these

morphological and functional anomalies – and improve the

symptoms of some of these conditions – now appear feasible.

This paper reviews recent findings on the functions of some of

the genes responsible for intellectual disability syndromes.

Addresses1 CNR Institute of Neuroscience, Department of Pharmacology,

University of Milan, Via Vanvitelli 32, 20129 Milan, Italy2 Neuromuscular Diseases and Neuroimmunology, Neurological Institute

Foundation Carlo Besta, Milan, Italy

Corresponding author: Sala, Carlo ([email protected])

Current Opinion in Neurobiology 2012, 22:530–536

This review comes from a themed issue on

Synaptic structure and function

Edited by Morgan Sheng and Antoine Triller

Available online 13th October 2011

0959-4388/$ – see front matter

# 2011 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.conb.2011.09.007

IntroductionAberrant synaptic formation signalling and plasticity, or

altered spine morphology, characterize several psychiatric

and neurological diseases [1] and it is now clear that

precise control of synaptic development is crucial for

the formation of a normally active neuronal network

allowing normal brain function.

Intellectual disability (ID), formerly mental retardation,

is one of the most common neurodevelopmental dis-

orders; it is characterized by an intelligence quotient of

70 or below and deficits in behaviors related to adaptive

functioning, including autism spectrum disorders (ASD).

Although in up to 60% of cases no cause has been

identified, in over 25% of cases ID is caused by genetic

factors [2]. A recent study found that ASD patients had a


high global burden of rare copy number variants especi-

ally of loci known to be associated with ASD, and also of

new genes previously unconnected with ASD [3��].

Over the past 15 years, many single-gene causes of

syndromic or nonsyndromic ID have been identified,

the most common of which are located on the chromo-

some X and are responsible for X-linked intellectual

disabilities (XLID). Over 50% of the ID-related proteins

that are not transcription or chromatin-remodelling fac-

tors, are conspicuously present in the pre-synaptic or post-

synaptic compartments and seem to be involved in synap-

tic actin cytoskeleton rearrangement, synaptic plasticity

or synapse formation [4].

It is useful to divide synapse-related proteins associated

with ID into those that localize purely at synapses

(mutations to which directly interfere with synaptic for-

mation) and other proteins that regulate neuronal de-

velopment and synapse formation indirectly by

controlling the synthesis, degradation or modulation of

synaptic proteins or the synaptic actin cytoskeleton. The

molecular mechanisms (Figure 1) by which alterations in

some of these proteins contribute to ID constitute the

main topic of this review.

X-linked gene mutationsFragile-X and Rett syndromes are responsible for most

forms of XLID. However mutations to several other

genes on chromosome X have been found strongly associ-

ated with ID, including mutations to the neuroligin genes

NLGN3 and NLGN4, which were among the first to be

clearly associated with synaptic function [5].

Neuroligins were first identified as binding partners of

neurexins. Later neuroligins and neurexins were found to

associate in synapses to form a trans-synaptic complex

crucial for synapse formation and function.

IL1RAPL1

Mutations of the interleukin-1 receptor accessory protein-

like 1 gene (IL1RAPL1) are associated with cognitive

impairment ranging from nonsyndromic ID to ASD [6–9]. IL1RAPL1 belongs to new Toll/IL-1 receptor family

and shares 52% homology with the IL-1 receptor acces-

sory protein (IL-1RacP). Like other members of this

family, IL1RAPL1 has three extracellular Ig-like

domains, a transmembrane domain, and an intracellular

Toll/IL-1R homology domain (TIR domain). Unlike

other family members, however, IL1RAPL1 has 150

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http://dx.doi.org/10.1016/j.conb.2011.09.007

Synaptic defects in intellectual disability Verpelli and Sala 531

Figure 1

Current Opinion in Neurobiology

Excitatory synapseand spine formation

NMDAR AMPAR

RhoGAP2

FMRP

MeCP2PSD-95

Homer tetramer

Shank

GKAP

JNK

OPHN1

OPHN1Rev-erbα

CASK

NLG

neurexin

TARP

IL1RAPL1

mGluR5

SER

IP3R

Synaptic proteindegradation

Circadian clockSynaptic proteinsynthesis

Synaptic receptorsignalling

PTPδ

The figure proposes a schematic organization of the protein network in excitatory synapses. The mainly synaptic proteins whose mutations are associated

with ID and are discussed in this review are shown underlined. Recently described major synaptic signalling defects are indicated in the boxes.

additional amino acids at the C-terminus. It has been

shown that IL1RAPL1 interacts with neuronal calcium

sensor-1 through its intracellular region [10], and that this

interaction mediates the regulatory effect of IL1RAPL1

overexpression on N-type voltage-gated calcium channel

activity in PC12 cells [11].

We recently showed that IL1RAPL1 binds postsynaptic

density protein 95 (PSD-95) and regulates its phosphoryl-

ation and synaptic association by activating c-Jun terminal

kinase (JNK) [12]. We also found that the extracellular

domain of IL1RAPL1 induces presynaptic differentiation

by binding the receptor tyrosine phosphatase d (PTPd),

localized at the presynaptic terminal, while the TIR

domain binds to RhoGAP2 and regulates dendritic spine

formation [13]. Yoshida et al. [14] also recently reported that

IL1RAPL1 and PTP-DELTA interact, but showed in

addition that the interaction was confined to particular

splice variants of PTPd. These findings suggest that the


IL1RAPL1 mediates trans-synaptic signalling that

regulates excitatory synapse and dendritic spine formation.

Thus it seems that even small changes in these synaptic

adhesion proteins can cause major changes in connectivity,

resulting in cognitive impairment. Interestingly, most of the

adhesion molecules found associated with ID regulate

excitatory synapse formation, and the resulting functional

alteration or reduction in number of excitatory synapses

arising from mutations, may alter the balance between

excitatory and inhibitory synapses leading to a general over-

inhibition within neuronal circuits as proximate cause of ID.

Oligophrenin-1

Mutations or deletions in the synaptic RhoGTPase-activat-

ing protein oligophrenin-1 are also associated with certain

forms of XLID [15] and constitute the main evidence that

signalling involving member A of the Ras homologue gene

family (RhoA) is involved in ID. Oligophrenin-1 is a


532 Synaptic structure and function

negative regulator of RhoA and also interacts with the

postsynaptic adaptor protein Homer [16]. Govek et al.[16] showed that oligophrenin-1 knockdown in CA1 pyr-

amidal neurons significantly reduces spine length, an effect

mimicked by a constitutively active form of RhoA, and

rescued, in the presence of constitutively active RhoA, by

inhibiting the RhoA effector Rho-kinase (ROCK1). Since

ROCK1 plays key role in RhoA-induced actin reorganiza-

tion, these findings implicate RhoA in regulating the actin

cytoskeleton of spines, probably through effects on LIM

kinase, myosin light chain (MLC), or MLC phosphatase

[15,16]. Thus, loss of oligophrenin-1 probably causes

changes in spine morphology during development due to

alteration of the actin cytoskeleton caused by loss of

repression of RhoA and ROCK1. Khelfaoui et al. [17] later

showed that oligophrenin-1-deficient mice have behavioral

deficits. A subsequent study showed that activation of

synaptic NMDA receptors localizes oligophrenin-1 to den-

dritic spines, where it forms a complex with AMPA recep-

tors and selectively enhances AMPA-receptor-mediated

transmission and spine size by stabilising those receptors

[18]. That oligophrenin-1 stabilizes AMPA receptors in

synapses is suggested by reduced number and activity of

such receptors in oligophrenin-1 KO mice, defects which

are rescued by blocking AMPA receptor endocytosis – in

turn indicating a link between oligophrenin-1/RhoA signal-

ling and AMPA receptor endocytosis [18]. Another study

has shown that oligophrenin-1 is concentrated at endocytic

sites and regulates AMPA receptor endocytosis at excit-

atory synapses by RhoA/ROCK signalling [19].

Very recently oligophrenin-1 has been shown to interact

with the circadian clock protein Rev-erba regulating its

circadian activity, suggesting that interaction between

synaptic activity and circadian oscillators can be involved

in the etiology of intellectual disability [20��]. Thus

oligophrenin-1 seems to have multiple functions in reg-

ulating synaptic activity and plasticity.

Fmrp

The fmr1 gene encodes the fragile X mental retardation

protein (FMRP). Failure to express FMRP results in fragile

X syndrome, leading cause of congenital ID in humans.

Patients with this syndrome have more, longer and thinner

dendritic spines than normal [21]. FMRP belongs to the

heterogeneous nuclear ribonucleoprotein family of RNA-

binding proteins; it regulates the transport to synapses and

translation of a subset of neuronal mRNAs [21–23] and its

expressionand localization to dendrites increase after synap-

tic stimulation, suggesting a direct link between FMRP and

synaptic plasticity [24–26]. The translational dysregulation

of target mRNAs that occurs when FMRP is not expressed

appears to be the main cause of the dendritic spine and

synapsealterations thatcharacterize fragileXsyndrome [23].

In fmr1 KO mice, DHPG-induced long term depression

(LTD) is strongly increased [27] and at the same time


metabotropic glutamate receptor (mGluR)-dependent

local protein synthesis is deregulated [27–30] The latter

finding has inspired the ‘mGluR theory’ of fragile X

syndrome: that alterations in mGluR-mediated signalling

might underlie the cognitive deficits of the syndrome, so

mGluR inhibitors might be useful as treatment [31].

The translation of several proteins is increased in fmr1 KO

mice, particularly in purified synaptosomes [29,30,32–35].

Schutt et al. [36] found that expression levels of the

postsynaptic scaffold proteins SAPAP1-3, Shank1,

Shank3, and IRSp53, as well as of the NR1 and NR2B

subunits of the NMDA receptor and GluR1 subunit of the

AMPA receptor are increased in cortex and hippocampus

of fmr1 KO mice. FMRP is also a negative regulator of

transcripts of the NR2A subunit of NMDA – a regulation

influenced by the microRNA miR-125b. These findings

suggest that FMRP absence alters synaptic plasticity in

fragile X syndrome by altering NMDA receptor subunit

composition [37�].

PSD-95 – key regulator of synaptic signalling and learning

– may be one of the more important synaptic proteins

regulated by FMRP. In fmr1 KO mice, PSD-95 mRNA and

protein levels are lowered in hippocampus but not cortex

[28]. However FMRP appeared to exert its effect by

stabilising PSD-95 mRNA, a new FMRP function [28].

Another study indicated that FMRP regulates mGluR

activation-dependent and microRNA dependent trans-

lation of PSD-95, CaMKIIa, and GluR1/2 in cortex [30].

Phosphorylated FMRP promotes the formation of an

AGO2-miR-125a inhibitory complex on PSD-95 mRNA

that is released by mGluR1 activation, causing FMRP to

dephosphorylate. These findings indicate that FMRP

phosphorylation provides a reversible switch for AGO2

and microRNA to selectively regulate mRNA translation

at synapses in response to receptor activation [30]. Dys-

regulated PSD-95 translation at synapses could, there-

fore, be responsible for the altered synaptic plasticity and

dendritic spine morphology of fmr1 KO mice [21]. How-

ever proteomic analysis of the entire synaptosome is

required to fully elucidate the role of FMRP and its

mRNA targets at synapses.

MECP2

Over 90% of Rett syndrome cases are caused by a

mutation on the MECP2 gene, which encodes methyl-

CpG-binding protein-2 (MeCP2), a protein that binds

methylated DNA and thereby influences gene transcrip-

tion. Early functional studies suggested that MeCP2

functioned as a molecular link between DNA methyl-

ation, chromatin remodelling and subsequent gene silen-

cing [38]. More recent studies indicate that MeCP2

represses the transcription of some genes yet promotes

the transcription of others; [39] it may even control the

AKT/mTOR signalling pathway and protein translation,



suggesting that defects in the AKT/mTOR pathway are

responsible for altered translational control in MeCP2

mutant neurons [40�].

Whatever MeCP2’s precise function, experimental

models involving both loss and gain of function of the

mouse mecp2 gene are characterized by numerous changes

in the morphology and function of neurons and synapses,

accompanied by severe neurodevelopmental defects and

behavioral alterations analogous to those in humans [41–43]. Furthermore, direct evidence of MeCP2 involve-

ment in the regulation of synaptic connectivity comes

from post-mortem studies [42,44], which reveal that

hippocampal CA1 pyramidal neurons from Rett syn-

drome females have lower spine density than age-

matched non-Rett syndrome female controls [42,44],

and that the syndrome is associated with abnormalities

in the expression of molecules crucial for excitatory and

inhibitory synaptic transmission [42,44].

MeCP2 also appears important for activity/experience-

dependent synaptic remodelling. Li et al. generated

knock-in mice that lacked activity-induced MeCP2 phos-

phorylation and found that the mice did better in hippo-

campus-dependent memory tests, had enhanced long-

term potentiation and had increased excitatory synapto-

genesis [45��]; the phospho-mutant MeCP2 protein also

bound more tightly to several MeCP2 target gene pro-

moters altering the expression of the genes. In mecp2-

deficient mice, retinogeniculate synapses developed sim-

ilarly to wild-type littermates between postnatal days 9

and 21, indicating that initial phases of synapse formation,

elimination, and strengthening were not affected by

MeCP2 absence [46�]. However, in the subsequent

experience-dependent phase of synapse remodelling,

the circuit became abnormal in mutants and synaptic

plasticity in response to visual deprivation was disrupted

[46�]. These findings point to MeCP2 as crucially

involved in experience-dependent refinement of synaptic

circuits, in line with the clinical course in Rett syndrome

patients, who after near-normal early development reach

a plateau followed by severe regression.

Synaptic scaffold proteinsSince PSD-95 is the most abundant scaffold protein at the

PSD, its gene – DLG4 in humans – has be extensively

studied for polymorphisms and mutations associated with

neurodevelopmental diseases. Only one study, however,

indicates an association between DLG4 gene variation

and ASD and Williams syndrome [47], while a haplotype

derived from 2 polymorphic markers at the core promoter

has been linked to schizophrenia [48].

By contrast, the human DLG3 gene, which encodes synapse-

associated protein 102 (SAP102) is clearly associated with

ID [49,50]. The mutations identified introduce premature

stop codons within or before the third PDZ domain,


probably impairing the ability of the truncated SAP102 to

interact with the NMDA receptor and other proteins

involved in NMDA receptor signalling pathways. A recent

publication demonstrated that SAP102 links NMDA re-

ceptor activation to alterations in spine morphology [51].

SHANK/ProSAP family

Phelan-McDermid syndrome (PMS, also called 22q13.3

deletion syndrome) is characterized by intellectual

impairment, absent or delayed speech, and autistic-like

behavior, as well as hypotonia and mild dysmorphic

features [52–55]. The deletion can be small but always

involves a crucial region that includes SHANK3 encoding

the Shank3/ProSAP2 postsynaptic scaffold protein. Loss

of Shank3 is now considered to cause the neurobehavioral

symptoms of PMS, although other genes may also be lost

[52,54,56,57]. De novo mutations in SHANK3 [57–59] and

also in SHANK2 [60] have been identified in individuals

with ASD and ID.

Mice lacking Shank1 have small dendritic spines, wea-

kened synaptic transmission, enhanced learning [61] and

defects in social communication [62]. Recent studies in

mice highlight the importance of Shank3 haploinsuffi-

ciency [63�,64�,65�,66�]. Thus male mice with heterozy-

gous or homozygous disruption of Shank3 had abnormal

behavior, learning and memory, compared to wild-type

littermates [64�,66�]. At the level of the synapse, these

animals had markedly impaired basal synaptic trans-

mission in CA3-CA1 connections, reduced GluR1 clusters

and protein levels in hippocampus, and altered activity-

dependent AMPAR synaptic plasticity [64�,66�].

Mice with genetic deletion of two major Shank3 splice

variants exhibit self-injurious repetitive grooming and

deficits in social interaction correlating with major altera-

tion in striatal synapses and cortico-striatal circuits, but not

in hippocampus, suggesting that the remaining Shank3

splice variant(s) may be sufficient to maintain normal

synapse function and structure in hippocampus [65�].

A mutated Shank3 protein that lacks the Homer-binding

C terminus induces a gain-of-function phenotype, that

reduces Shank3 expression at synapses by >90% owing to

greater polyubiquitination. The NR1 subunit of the

NMDA receptor is also reduced at synapses by greater

polyubiquitination, while AMPAR function and compo-

sition are not affected [63�].

We knocked down all major Shank3 splice variants in

rodent neuronal cultures by RNA interference [67] and

found that Shank3 knockdown in hippocampal cells

reduced the expression of mGluR5 receptors, and also

reduced DHPG-induced phosphorylation of ERK1/2 and

CREB. The overall result was reduced mGluR5-depend-

ent synaptic plasticity and modulation of neural network

activity.



Together these studies show that mutations in Shank3

cause alterations in both synaptic morphology and

signalling.

Therapeutic prospectsMolecular mechanisms contributing to the pathogenesis

of various types of genetically determined ASD and ID

suggest new targets for the development of drugs to

ameliorate these conditions. Since ProSAP/Shank disrup-

tion seems to lead to a hypoglutamatergic state, upregu-

lation of the glutamatergic system may be a promising

therapeutic approach. In particular, agents that activate

synaptic currents mediated by AMPA-type glutamate

receptors (AMPAkines) could prove useful [68]. AMPA-

kines improve the induction of long-term potentiation

and exert a positive effect on excitatory transmission by

upregulating the production of regulated brain-derived

neurotrophic factor (BDNF) which is involved in synaptic

plasticity and memory consolidation [69]. In view of the

deficit in mGluR5-mediated intracellular signalling found

in Shank3 knockdown neurons, use of positive allosteric

modulators of mGluR5 – for example CDPPB – suggests

itself as a pharmacological approach to these conditions

[67].

Environmental enrichment is a radical non-pharmaco-

logic approach to ASD. Animals reared under environ-

mental enrichment conditions have enhanced synapse

formation and plasticity and increased BDNF expression

[70] and environmental enrichment promotes synaptic

plasticity and regulates synapse stability in the cerebral

and cerebellar cortex of MeCP2 null mice [71].

Another possible approach to rescuing synaptic defects in

patients with ID is to use human induced pluripotent

stem cells (hiPSC) as suggested by the work of Marchetto

et al. [72��] These authors cultured hiPSCs from the

fibroblasts of patients with Rett syndrome and tested

drugs on the culture with the aim of rescuing the evident

synaptic defects in the cells.

AcknowledgementsC.S. and C.V. were supported by grants Telethon – Italy (Grant No.GGP09196), Fondazione CARIPLO (Project number 2009.264), RegioneLombardia (Project number SAL - 50 - 16983 TERDISMENTAL), ItalianInstitute of Technology, Seed Grant and Ministry of Health in the frame ofERA-NET NEURON.

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39. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J,Zoghbi HY: MeCP2, a key contributor to neurological disease,activates and represses transcription. Science 2008,320:1224-1229.

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This study shows that rpS6 phosphorylation is severely affected incortical neurons of MeCP2 mutant mice and that defects in the AKT/mTOR pathway are responsible for altered translational control in MeCP2mutant neurons.

41. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L,Chen WG, Lin Y, Savner E, Griffith EC et al.: Brain-specificphosphorylation of MeCP2 regulates activity-dependent Bdnftranscription, dendritic growth, and spine maturation. Neuron2006, 52:255-269.

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Li H, Zhong X, Chau KF, Williams EC, Chang Q: Loss of activity-induced phosphorylation of MeCP2 enhancessynaptogenesis, LTP and spatial memory. Nat Neurosci 2011.

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Noutel J, Hong YK, Leu B, Kang E, Chen C: Experience-dependent retinogeniculate synapse remodeling is abnormalin MeCP2-deficient mice. Neuron 2011, 70:35-42.

The study investigates retinogeniculate synapse maturation in MeCP2-deficient mice showing that synapse development in these mutants issimilar to that of wild-type animals. However during the subsequentexperience-dependent phase of synapse remodeling, the circuitbecomes abnormal in mutants and synaptic plasticity, in response tovisual deprivation, is disrupted.

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58. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J,Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P et al.:Contribution of SHANK3 mutations to autism spectrumdisorder. Am J Hum Genet 2007, 81:1289-1297.

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This and the following three studies describe multiple synaptic andbehavioral defects in mice in which major splice variants of Shank3 havebeen knocked out.

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Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL,Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML et al.:Haploinsufficiency of the autism-associated Shank3 geneleads to deficits in synaptic function, social interaction, andsocial communication. Mol Autism 2010, 1:15.

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Wang X, McCoy PA, Rodriguiz RM, Pan Y, Je HS, Roberts AC,Kim CJ, Berrios J, Colvin JS, Bousquet-Moore D et al.: Synapticdysfunction and abnormal behaviors in mice lacking majorisoforms of Shank3. Hum Mol Genet 2011.

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Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y,Chen G, Gage FH, Muotri AR: A model for neural developmentand treatment of Rett syndrome using human inducedpluripotent stem cells. Cell 2010, 143:527-539.

This study demonstrates for the first time the use of hiPSC to recapitulateearly stages of human Rett syndrome and shows how this tool can beused as a cellular model for drug screening.
