Articulo Molecular

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, ,

*Clnica Psiquiatrica Universitaria, Hospital Clnico de la Universidad de Chile, Casilla,Santiago, Chile

Laboratorio de Neurociencias Cognitivas, Departamento de Psiquiatra,Escuela de Medicina, Pontificia

Universidad Catolica de Chile, Chile

Programa de Genetica Humana, Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de

Chile, Santiago, Chile

Schizophrenia is a common chronic mental disease with an

unknown etiopathogenic framework. The dominant working

model in schizophrenia postulates that genetic (Stefansson

et al. 2008; Walsh et al. 2008) and environmental (Fatemi

et al. 2000) neurodevelopmental disturbances may lead to

dysfunctional neuronal migration, the disorganized cytoar-

chitecture of cortical layers and synaptic alterations that

become associated with schizophrenia (Harrison 1999;

Harrison and Weinberger 2005). The structural consequence

of these disturbances is an altered brain connectivity, also

called neuronal disconnectivity (Friston 1998; Stephanet al.

2006). Disconnectivity may be assessed at different structural

and functional levels in the brain, from alterations in tract

integrity to functional deficits in neuronal integration (Gaspar

et al. 2009). Functional consequences of disconnectivity

involve: (i) an altered timing of firing rate at the synaptic

level; (ii) delayed coupling of synaptic neurotransmission at

neurochemical pathways; and (iii) a loss of rhythm synchro-

nization of brain oscillations at system levels involving brain

communication. All these mechanisms have been described

in this disease (Gasparet al.2009). However, it is important

to mention that there is also evidence for an increased

connectivity in some domains of the schizophrenic brain. For

this reason, we have previously preferred the term aberrant

connectivity to describe the neuropathological condition

Received June 7, 2009; accepted July 28, 2009.

Address correspondence and reprint requests to Pablo A. Gaspar,

Clnica Psiquiatrica Universitaria, Hospital Cl nico de la Universidad de

Chile Av. La Paz 1003-Recoleta, Casilla 70014, Chile.

E-mail: [email protected]

Abbreviations used: mGluR, metabotropic glutamate receptor;

NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor; NRG1,

neuregulin-1; PSD, post-synaptic densities.

Abstract

Early models for the etiology of schizophrenia focused on

dopamine neurotransmission because of the powerful anti-

psychotic action of dopamine antagonists. Nevertheless, re-

cent evidence increasingly supports a primarily glutamatergic

dysfunction in this condition, where dopaminergic disbalance

is a secondary effect. A current model for the pathophysiology

of schizophrenia involves a dysfunctional mechanism by

which the NMDA receptor (NMDAR) hypofunction leads to a

dysregulation of GABA fast- spiking interneurons, conse-

quently disinhibiting pyramidal glutamatergic output and dis-

turbing the signal-to-noise ratio. This mechanism might

explain better than other models some cognitive deficits ob-

served in this disease, as well as the dopaminergic alterations

and therapeutic effect of anti-psychotics. Although the mod-

ulation of glutamate activity has, in principle, great therapeutic

potential, a side effect of NMDAR overactivation is neurotox-

icity, which accelerates neuropathological alterations in this

illness. We propose that metabotropic glutamate receptors

can have a modulatory effect over the NMDAR and regulate

excitotoxity mechanisms. Therefore, in our view metabotropic

glutamate receptors constitute a highly promising target for

future drug treatment in this disease.

Keywords: GABA, glutamatergic hypothesis, mGluR,

NMDAR, schizophrenia, treatment of schizophrenia.

J. Neurochem. (2009) 111, 891900.

JOURNAL OF NEUROCHEMISTRY | 2009 | 111 | 891900 doi: 10.1111/j.1471-4159.2009.06325.x

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underlying schizophrenia, where some functional domains

(particularly those related to certain cognitive and perceptual

processes) are impaired by disconnectivity, while others (for

example, the so-called default network) display an abnor-

mally increased connectivity (Gasparet al. 2009; Whitfield-Gabrieliet al. 2009).

Although there seems to be general agreement about the

disturbances of connectivity in the schizophrenic brain, there

is an agitated controversy over the neurochemical mecha-

nisms underlying the pathophysiology of this disease. Two

main proposals have been raised in this context: the

dopaminergic hypothesis and the glutamatergic hypothesis.

In our view, recent evidence strongly points to the latter as

the principal mechanism in this condition. In this article, we

will review the evidence for the glutamatergic hypothesis of

schizophrenia, and will discuss possible therapeutic strate-

gies oriented at modulating glutamate activity via metabo-

tropic glutamate receptors (mGluRs).

The glutamatergic hypothesis in schizophrenia

The dopaminergic hypothesis, implying a hyperactivity of

the dopaminergic system, was the principal neurochemical

hypothesis of schizophrenia until recently (Snyder et al.

1974; Carlsson et al. 2004). This hypothesis was mainly

based on the fact that all typical anti-psychotics exert their

effects principally by blocking D2 dopamine receptors

(Seeman 2006) and that stimulants enhancing dopaminergic

neurotransmission may induce some positive schizophrenia-

like symptoms in normal human volunteers, and exacerbatedpsychotic symptoms in schizophrenic patients (Angrist and

Sudilovsky 1978). However, direct support for this proposal

has been elusive (Iversen and Iversen 2007).

On the other hand, evidence has accrued over the past

years that points to a specific malfunction of glutamatergic

receptors in the etiology of schizophrenia (Kim et al. 1980;

Javitt 1987). Glutamate is the main excitatory neurotrans-

mitter in the brain and is essential for sensorimotor and

cognitive circuitry, which participates in development, syn-

aptic plasticity, neuroprotection and glial-neuronal commu-

nication. Glutamate acts on two major classes of receptors:

ionotropic glutamatergic receptors: AMPA, NMDA and

Kainate, which are ligand-gated ion channels; and mGluRs

(Masu et al. 1993). In general terms, the glutamatergic

hypothesis of schizophrenia states that hypofunction of this

neurotransmitter in cortico-striatal projections provokes a

facilitation of thalamo-cortical circuits, producing an

augmented sensory input, a decrease in the signal-to-noise

ratio and an increase in dopaminergic input because of the

disinhibition of the ventral tegmental area in the mesenceph-

alon (Lang et al. 2007). Another possibility, although not

strictly an alternative to that above, is that a malfunction of

NMDA receptors (NMDARs) in GABAergic interneurons

generates a generalized disinhibition in the cerebral cortex

(Stahl 2007; Lisman et al. 2008). In fact, alterations in

GABAergic interneurons, which receive strong inputs from

glutamatergic neurons, are one of the most reproducible

neuroanatomic alterations in schizophrenia (Lewis et al.

2005). In the next section, we will explore this second modelin some detail.

Part of the evidence that links glutamate receptors

(specifically NMDARs) and schizophrenia is that (i) the

use of the NMDAR antagonists (MK-801, phencyclidine and

ketamine) in rats and humans closely mimics the positive,

negative and cognitive symptoms observed in schizophrenia,

perhaps better than any other known drug (Krystal et al.

1994; Carlssonet al.2004; Lismanet al.2008), and worsens

the positive symptoms in chronic- and non-medicated

patients (Lahtiet al.1995; Medoffet al.2001). Furthermore,

subanesthetic doses of ketamine correlate with impaired

performance on the Wisconsin Card Sorting Test, on spatial

and verbal working memory tasks and on verbal declarative

memory tasks (Krystal et al. 2000; Rowland et al. 2005),

and produce alterations commonly observed in schizophren-

ics such as a decreased amplitude in event-related potentials

(Umbrichtet al. 2002). Besides, (ii) drug treatments target-

ing the glutamatergic receptors improve the clinical state of

patients even more efficaciously than drugs that selectively

target the monoaminergic system (Malhotra et al. 1997;

Conn et al. 2009); and (iii) a strong decrease of the

transcripts related to glutamatergic and GABAergic neuro-

transmission has been consistently observed in schizophrenia

by using DNA microarray techniques (Mirnics et al. 2000;

Frankle et al. 2003). Furthermore, (iv) functional neuroi-maging studies provide evidence of the dysregulation of

glutamatergic pathways in schizophrenic patients (van Elst

et al.2005; Gozziet al.2008). Finally, (v) at a systems level,

neuronal synchronization that is thought to depend partly on

glutamatergic regulation over GABAergic neurons is im-

paired in schizophrenia (Fordet al.2007) and correlates with

perceptual, speech and other cognitive processes (Spencer

et al. 2003; Lewis et al. 2005; Mohler 2007; Gasparet al.

2009). Therefore, the identification of the molecular altera-

tions that generate this glutamatergic dysfunction is crucial

for understanding the physiopathology of this disease and

planning the future of drug treatment. Considering this

evidence, several authors now agree that dopaminergic

dysfunction may be secondary to an underlying glutama-

tergic dysfunction (Tuominen et al. 2005; Lisman et al.

2008).

Therefore, the study of glutamatergic regulation in

schizophrenia, particularly of the glutamatergic receptors

and their intracellular pathways, might yield important

information on the physiopathology of this disease. Further-

more, in order to prevent and stop the progression of

disconnectivity in this disease, it may be especially important

to discover molecules that regulate glutamatergic activity in

these networks.

892 | P. A. Gaspar et al.

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NMDAR hypofunction and its consequences forschizophrenia

As mentioned, a current model for NMDA participation in

schizophrenia implies that, in conditions of NMDARdysfunction, the glutamatergic pyramidal neurons of the

cerebral cortex lose the tonic regulation by fast-spiking

GABAergic interneurons (the latter are normally stimulated

by NMDAR), leading to a generalized increase of firing rate

in pyramidal neurons. Since pyramidal glutamatergic and

fast-spiking GABAergic interneurons have been proposed to

represent a basic circuit of oscillatory synchronous activity

(Bartos et al. 2007), this decrease in GABAergic function

leads to a decrease in the functional connectivity or

integrative capacity in the cortical networks. High-frequency

synchronic activity correlates with several cognitive pro-

cesses such as working memory and attention (Tallon-

Baudry et al. 1998, 2001; Womelsdorf and Fries 2006).

Working memory deficits have been considered an essential

feature in the physiopathology of this disease and could be a

clinical trait to be tested in genetic and neurochemical

models in schizophrenia (Goldman-Rakic 1994; Green and

Nuechterlein 1999). Such alterations have been consistently

observed when assessing spatial and verbal domains in

schizophrenics (Hugueletet al. 2000; Conklin et al. 2005),

during crisis and compensated states (Park et al. 2002), in

first-episode patients and patients with prodromal symptoms

(Albus et al. 1996; Eastvold et al. 2007) and in high-risk

populations for schizophrenia (Asarnow 1999; Erlenmeyer-

Kimling 2000). Therefore, the study of working memoryalterations may provide a window to analyze the cognitive

deficits in schizophrenia (Fig. 1).

A second consequence of the loss of GABAergic modu-

lation is a direct mechanism of neurotoxicity through non-

NMDAR signaling (Lisman et al. 2008). All mechanisms of

neurotoxicity described in schizophrenia involve the

malfunction of the NMDAR. These mechanisms include (i)

direct hypofunction of the NMDAR (Wang et al. 2000), (ii)

mitochondrial dysfunction (Ben-Shachar 2002) and (iii)

disinhibition of glutamatergic pyramidal neurons from

GABAergic modulation (Lewis et al. 2005) (see Fig. 1).This proposal has received support from animal models

displaying increasing glutamate levels after the long-term

exposition of several antagonists of the NMDAR such as

phencyclidine (Wang et al. 2000) and ketamine (Moghad-

damet al. 1997). Furthermore, it has been observed that the

chronic exposure of NMDAR antagonists induces neurotox-

icity (Wang et al. 2001). These observations have led to the

proposal of a mechanism of up-regulation of the NMDAR

under these conditions. In this way, the direct treatment of

schizophrenia based on NMDAR antagonists could trigger a

secondary cascade of events, which could lead to toxicity

mechanisms and provoke the opposite effect, accentuating

the disconnectivity processes. So, the excitotoxicity associ-

ated with directly balancing glutamate levels through

NMDAR agonist-antagonist modulation limits its therapeutic

potential. Thus, other kinds of regulation should be studied to

generate safer therapeutic approaches based on NMDAR

regulation. With this idea in mind, we will analyze the

downstream pathways of the NMDAR and how these may

contribute to understanding NMDAR hypofunction in

schizophrenia. Then, on the basis of growing evidence we

will propose that mGluRs are a possible therapeutic target in

schizophrenia.

NMDAR and its altered intracellular pathway inschizophrenia

The NMDARs participate as mediators of excitatory post-

synaptic currents, a voltage-dependent mechanism critical for

learning, working memory and attention (Coyle et al.2003).

The activity of these receptors is usually regulated by a

Dopaminergic and

colinergic output

mGLUR5

mGLUR2/3

mGLUR2/3

NMDAR

AMPA (a)

(b)

(c)

GABA-FS-interneuron

Glutamatergic excitatory

output

Excitatory output

Inhibitoryoutput Pyramidal glutamatergic

neuron

Fig. 1 Basic circuit of the neurochemical

pathways involved in schizophrenia. The

critical circuit involves the participation of

GABA fast-spiking interneurons (b) and

glutamatergic pyramidal neurons (c). Alter-

ations in all the molecular mechanisms in

this circuit, including NMDA, AMPA and

mGluR receptors (a and b) and their intra-

cellular pathways could lead to network

dysfunction. Besides, alterations in acetyl-

choline (Ach) and/or dopamine neurotrans-

mission could also participate in the

physiopathology of this disease by modu-

lating these circuits.

Glutamatergic hypothesis in schizophrenia | 893

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voltage-dependent and magnesium-dependent mechanism.

Furthermore, the expression of the NMDAR genes are

modulated by the activity of the receptor itself, which allows

calcium entry into the cell, triggering a cascade leading to

gene activation. This regulation is the basis for the mech-anism of synaptic long-term potentiation and associated

morphological changes such as the growth of dendritic

buttons that occurs during persistent stimulation of the

pyramidal glutamatergic neurons (Lau and Zukin 2007).

Many endogenous ligands of the NMDAR regulate the

activity of this receptor. Especially important in this context

is the glycine modulatory site present in this receptor because

of its possible therapeutic implications for schizophrenia

(Laneet al. 2008).

Considering that malfunction of the NMDAR could lead

to brain excitotoxicity and several behavioral dysfunctions

(positive and negative symptoms in schizophrenia), the

normal function of the NMDAR must remain under tight

cellular regulation. The NMDARs are located in the post-

synaptic densities (PSD, cytoskeletal specializations that

include the scaffolding protein complex and other signaling

proteins). The PSD link the receptor to kinases, phosphatases

and other intracellular proteins related to mGluRs, as will be

described in the next section. Inside the PSD, the NMDAR is

associated with scaffolding proteins such as the PSD protein

of 95 KDa (PSD-95) and the synapse-associated protein of

102 KDa (SAP-102). These protein complexes are important

in the intracellular trafficking and synaptic delivery of

NMDAR (Scannevin and Huganir 2000). The number and

subunit composition of the NMDARs are tightly regulated inresponse of neuronal activity and sensory experience (Lau

and Zukin 2007). The NMDAR subunits NR1 and especially

NR2 confer most of the biophysical and pharmacological

properties to this receptor (Cull-Candy and Leszkiewicz

2004). One of the main mechanisms of regulation of the

NMDAR is the balance of phosphorylation in the intracel-

lular C-terminal domain of these subunits. A great number of

phosphatases regulate the phosphorylation levels of the

NMDAR, through non-receptor tyrosine kinases of the Scr

family (Salter and Kalia 2004). While phosphorylation of the

NR2b subunit of the NMDAR facilitates the suppression of

clathrin-mediated endocytosis of these receptors, dephos-

phorylation of this subunit triggers NMDAR internalization.

Controlling the phosphorylation levels of NMDAR signaling

is an important mechanism of glutamatergic receptor-depen-

dent synaptic plasticity (Lau and Zukin 2007).

As in many cellular types, the signal transduction pathway

of the NMDAR in glutamatergic neurons depends on the

activation of the mitogen-activated protein/NMDAR genes

are pathway (Fig. 2). This signaling is finished by a

mGluR I

mGluR II

mGluR III

Others

agonits

mGluR I

?

NMDA

NMDA

AMPA

AMPc

AMP SCRErk/MAPK

PKC

CDPPB

CPHG

Glycine

LY354740LY379268LY314582LY404039

D-serineD-Alanine

+

+

CREB

Ca+

Fig. 2 Glutamatergic neurotransmission and its possible therapeutic

targets in schizophrenia. Modulation of the NMDAR involves metab-

otropic receptors in pre- and post-synaptic clefts (mGluR), ionotropic

receptors (AMPA/Kainate) and agonists of NMDA. In the pre-synaptic

neuron, mGluR2 and mGluR3 inhibit the release of vesicular gluta-

mate. On other hand, mGluR1 induces vesicular release. In the post-

synaptic neuron, the modulatory role of mGluR1 over the NMDAR is

still under debate. According to the evidence reviewed in this work, all

the glutamatergic receptors (AMPA, NMDA and mGluR) are some-

how impaired in schizophrenia. The direct modulation of NMDA by

several agonists (glycine,D-alanine and D-serine) may have important

therapeutic implications. Additionally, the modulation of mGluR by

several molecules (LY354740, LY379268, LY314582, LY404039,

CDPPB and CPHG) could attenuate the effect of exacerbated

NMDAR neurotransmission because of the neuroprotective role of

mGluR (see text).



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downstream stop signal that involves the activation of the

striatal-enriched tyrosine phosphatase that regulates

extracellular signal-regulated kinases (ERK) signaling, a

mechanism mediated by Ca2+ influx (Paul et al. 2003).

Mechanisms for the rapid internalization of the NMDARmight explain the hypofunction of this receptor in schizo-

phrenia. As previously mentioned, the dephosphorylation of

the NMDAR NR2 subunit could produce internalization of the

NMDAR through a clathrin-dependent mechanism. It has

been recently described that the binding of neuregulin-1

(NRG1) to the ERBB4 receptor produces dephosphorylation

of the NR2A subunit, leading to an altered downstream

signaling of the NMDAR (Hahnet al.2006). NRG1 is one of

the four proteins of the neuregulin family that act on the family

of epidermal growth factor receptors. NRG1 induces prolif-

eration, migration, differentiation and apoptosis in different

cell types during neurodevelopment, and participates in

synaptic plasticity (Buonanno and Fischbach 2001). Poly-

morphisms in NRG1 and its epidermal growth factor receptors

genes are linked with susceptibility to schizophrenia (Mei and

Xiong 2008) and could contribute to the structural and

functional disconnectivity in this disease (Gasparet al.2009).

Another mechanism for the augmented internalization of

the NMDAR in schizophrenia might involve the over-

activation of phosphatases in the NMDAR downstream

signaling. Serine/threonine Phosphatase PP2B, also known

as calcineurin, is a neuron-enriched phosphatase that regu-

lates synaptic plasticity and NMDAR neurotransmission.

PP2B dephosphorylates and activates striatal-enriched tyro-

sine phosphatase, which induces dephosphorylation of theNR2B subunit, promoting internalization of the NMDAR

(Braithwaiteet al.2006). Calcineurin knockout mice display

an increased locomotor activity, decreased social interaction

and impaired attention and working memory function (Zeng

et al. 2001; Miyakawa et al. 2003). A potential schizophre-

nia susceptibility gene, the calcineurin c catalytic subunit

(PPP3CC), has been detected (Gerber et al. 2003). A

significant association was reported between some haplo-

types ofPPP3CCwith a Taiwanese sample of schizophrenic

patients with deficits in sustained attention and executive

processing (Liu et al. 2007). In spite of these promising

results, another study failed to reproduce these findings

(Kinoshitaet al. 2005).

mGluRs: physiology and possible involvement inschizophrenia

The physiology and functional disturbances of mGluRs are

relevant topics to schizophrenia since these molecules may

have a direct etiopathogenic role on the disorder, but also

because as mentioned they may represent useful therapeutical

targets to mitigate glutamatergic dysfunction, therefore,

alleviating the symptoms of this condition (Moghaddam

2004).

Ligand-gated ion channels (NMDA and AMPA receptors)

are responsible for fast excitatory transmission, while

mGluRs have a modulatory role (Cartmell and Schoepp

2000; Gasparini et al. 2008). mGluRs are subdivided into

three classes according to pharmacological and cell signalingproperties.

Group I mGluRs (mGluR1 and mGluR5) are expressed

mainly at post-synaptic sites. They activate phospholipase C to

generate diacylglycerol and inositol 1,4,5-triphosphate, there-

fore, increasing the release of calcium from endoplasmic

reticulum, which results in protein kinase C activation. These

receptors also potentiate L-type calcium channels and inhibit

potassium channels, and may also activate other transducing

cascades that trigger phosphorylation of ion channels, tran-

scription factors and other target proteins. Through these

mechanisms, group I mGluRs increase neuronal excitability

and promote long- and short-term plasticity (Benarroch 2008).

Activation of group II mGluRs (mGluR2 and mGluR3)

and group III mGluRs (mGluR4, mGluR6, mGluR7 and

mGluR8) determines changes on adenylyl cyclase activity

and, therefore, on the levels of cAM1P and activity of protein

kinase A. Although this coupling seems region-specific, the

primary action of group II and group III mGluRs is the

decrease of cAMP and protein kinase A activity. (Kim et al.

2008). Aside from their specific mechanisms of action, all

families of mGluRs converge on the activation of mitogen-

activated protein kinases. This effect is also relevant for long-

term plasticity (Kim et al. 2008).

Different glutamatergic pathways interact with each other.

At the post-synaptic densities, mGluR5 is physically linkedto the NMDAR via homer, shank and PSD-95 (Gray et al.

2009). Group I mGluRs induce the enhancement of NMDAR

currents and are involved in the direct phosphorylation of the

NMDAR (Pisani et al. 2001; Homayoun et al. 2004).

However, other authors have found that activation of these

receptors reduces nerve cell death caused by exposure to

NMDAR agonists (neuroprotective effect), and could facil-

itate neurogenesis through a reduction of NMDA-stimulated

currents (Baskys et al. 2005). On the other hand, activation

of group II and group III mGluRs involved in the regulation

of the release of glutamate and other neurotransmitters

(Cartmell and Schoepp 2000) may generate neuroprotection.

Such an effect has been evident in some neurotoxicity

models (Vernon et al. 2008).

Metabotropic glutamate receptors also link the glutama-

tergic pathway with other neurotransmitter systems, as they

modulate GABA and dopaminergic activity (David and

Abraini 2002; Durand et al. 2008). Genetic studies suggest

that mGluRs may be directly involved in the pathogenesis of

schizophrenia. The strongest evidence points to the associ-

ation of variants of the Glutamate receptor, metabotropic, 3

(GRM3) gene, which codes mGluR3, with the diagnosis of

schizophrenia or with some cognitive features of it (Harrison

and Weinberger 2005). Association has also been shown with


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a gene whose product is involved in metabotropic signaling

regulation, the regulator of G protein signaling 4 (RGS 4)

gene (Levittet al.2006). Association studies involving other

mGluRs are scant and several of them have produced

negative results (Bray et al. 2000; Bolonna et al. 2001;Takaki et al. 2004; Fallin et al. 2005; Ohtsuki et al. 2008).

When gene expression has been studied, no changes in

mRNA levels of mGluR3 have been found (Harrison et al.

2008), however, one relevant finding is that even when the

total amount of the protein mGluR3 is preserved, its dimeric

form was found to be decreased (Corti et al. 2007). Other

studies have focused on protein expression in several brain

regions and found abnormalities involving mGluR1a and

mGluR2/3 in the prefrontal cortex of schizophrenic patients

(Guptaet al. 2005).

Neuropathological and behavioral disturbances have been

observed in knockout animals for different mGluR families

(Linden et al. 2002; Brody et al. 2003, 2004; Cryan et al.

2003; Lyonet al.2008; Grayet al.2009). From this finding,

one may speculate that these molecules are in fact involved

in the pathogenesis of schizophrenia. Alternatively, these

findings may be an indication that modifications affecting

them have consequences that could be useful for clinical

practice. We adhere to this second line of thought.

In accordance with this, pharmacological studies at the

pre-clinical and clinical levels show that mGluR-modulatory

drugs may be useful in alleviating the features of schizo-

phrenia and other neuropsychiatric disorders, such as cog-

nitive disturbances and anxiety (Gray et al. 2009; Kinney

et al.2003, 2005; Krystal et al.2005; Pietraszeket al.2005;Smialowskaet al. 2007; Lavreysen and Dautzenberg 2008;

Palucha-Poniewieraet al. 2008; Paz et al. 2008). Of partic-

ular interest is the study by Patil et al.(2007) that involved a

group II mGluR agonist administered as the pro-drug

LY2140023. Through a randomized, double blind, placebo

controlled study, this molecule was shown to be successful in

reducing positive and negative symptoms in schizophrenic

patients while being well tolerated. In general terms,

modulation of mGluRs may contribute to restore regulation

of glutamatergic system through the enhancement of

NMDAR activity (by enhancing mGluR5) or the reduction

of excitatory glutamatergic transmission at key synapses in

the prefrontal cortex (by enhancing mGluR2 and mGluR3).

Highly selective positive allosteric modulators of these

receptors may serve this purpose (Conn et al. 2009).

Concluding remarks

Neuroleptic treatment focused on monoaminergic targets has

enabled the control of the most common symptoms observed

in schizophrenics: hallucinations and delusions. Although

these kinds of symptoms, also known as positive, are

frequently associated with this illness, they are not the most

specific. Cognitive dysfunctions, such as attention, working

memory and executive functions, have been proposed as core

features of this disease (Goldman-Rakic 1994; Green 1996).

Cognitive deficits are present in first-episode patients, in a

high-risk populations of schizophrenia (Erlenmeyer-Kimling

2000) and are among the best predictors of deficits in dailyactivities and the long-term functional outcome of patients

(Addington et al. 1998; Dickinson and Coursey 2002).

Drugs that modulate the glutamatergic system can have an

effect on the stabilization of not only positive, but also

negative symptoms and cognitive deficits observed in

schizophrenia. As we discuss in this article, NMDAR may

play a central physiopathological role in this disease.

Hypofunction of the NMDAR underlies the widely

distributed domains of disconnectivity in schizophrenia. As

commented in the introduction, the disconnectivity in

schizophrenia involves different domains depending on the

level of structural and functional integration in the brain. On

one side, we find poor connectivity looking for alterations in

the white matter tracts of the postmortem (Crow 1998;

Hoffman and McGlashan 1998) and in vivo schizophrenic

brain (Hubl et al. 2004; Shergill et al. 2007; Whitford et al.

2007). On the other side, disconnectivity can be understood

as an alteration of the temporal correlation of different groups

of neurons, named cell assemblies, which are not directly

connected to each other. This mechanism of connectivity has

been called neuronal synchronization, and has been found to

be strongly decreased in schizophrenia, at least during some

cognitive tasks (Spencer et al. 2003; Ford and Mathalon

2008). One possible mechanism for impairing functional

connectivity between different brain regions relates toalterations in the NMDAR located in the soma of fast-

spiking GABA interneurons of the prefrontal cortex (Lewis

et al.2005). Alterations in this target could explain working

memory disturbances through the disruption of neuronal

oscillations and synchronization (Gasparet al.2009). On the

other hand, the hypofunction of the NMDAR affecting

GABAergic interneurons in the thalamus, hippocampus and

prefrontal cortex would result in an increased glutamatergic,

cholinergic and dopaminergic release in the cortex and other

localizations (Olney and Farber 1995). These disbalances of

neurochemical pathways could explain many of the wide

ranging symptoms observed in schizophrenia. Note that as

previously mentioned, disconnectivity may be relevant in

some functional domains of the schizophrenic brain, but there

is also evidence for hyperconnectivity in other domains. Thus,

perhaps the term aberrant connectivity better fits the general

alterations of the schizophrenic brain (Gasparet al. 2009).

Considering this evidence, many efforts have been made

to develop drugs that target NMDAR, although the utility of

these agents is limited because of adverse effects that

manifest at the cellular and clinical levels. One of these

limitations relates to excitotoxic mechanisms triggered by

NMDAR stimulation pathways, affecting the GABAergic

cortical and hippocampal interneurons (Stone et al. 2007)



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and related pyramidal glutamatergic neurons among other

cell types.

As we have argued, mGluRs could become an important

target of new drug treatment in this disease based on their

regulatory role over the NMDAR and capacity to preventexcitotoxity mechanisms. Clinical trials are currently testing

some NMDAR-glycine site agonists and glycine transporter

inhibitors in schizophrenic patients, such as D-cycloserine

and sarcosine (N-methylglycine) respectively (Buchanan

et al. 2008; Lane et al. 2008). Biomolecules that target

mGluRs could help as an adjunctive therapy of direct

agonists of the NMDAR, and pre-clinical and clinical

evidence has been accumulating in this direction. One of

the most promising attempts is the administration of the pro-

drug LY2140023, which has been tested on schizophrenic

patients.

In conclusion, the aim of this work was to review the

glutamatergic hypothesis in schizophrenia, emphasizing an

update on the altered intracellular pathways of the NMDAR

and mGluRs, and the possibility of using them as targets in

the development of new drug treatments for cognitive deficits

in schizophrenia. Exhaustive clinical trials will be needed to

test this proposal.

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