Signaling pathways in schizophrenia: emerging targets and therapeutic strategies

doi:10.1016/j.tips.2010.05.004

Trends in Pharmacological Sciences

Volume 31, Issue 8, August 2010, Pages 381-390

https://doi.org/10.1016/j.tips.2010.05.004 Get rights and content

Dopamine D₂ receptor antagonism is a unifying property of all antipsychotic drugs in use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms. Increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. We review targeted approaches for pharmacotherapy involving the glutamatergic, GABAergic and cholinergic pathways. We also describe several of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention. These include genes in the 22q11 locus, DISC1, Neuregulin 1/ErbB4, and components of the Akt/GSK-3 pathway.

Section snippets

Schizophrenia, signaling and drug development

Schizophrenia is a debilitating psychiatric disorder that affects 1% of the worldwide population. It occurs as a sporadic and as a heritable disease, typically presenting in adolescence or early adulthood, and leads to great disability and distress. Characteristics include positive symptoms (delusions, hallucinations, and disorganized thought, speech and/or behavior), negative symptoms (amotivation, social withdrawal, poor relatedness and a reduction in affective expression) and cognitive

Glutamatergic signaling

NMDA antagonists such as phencyclidine (PCP) or ketamine exacerbate symptoms in people with schizophrenia, and even a single exposure can mimic the symptoms of schizophrenia in healthy controls and in animal models [4]. Although direct NMDA agonists cannot be used clinically, allosteric enhancers such as glycine, D-serine, or D-alanine have been used with mixed results [5]. The glycine transporter modulates the amount of glycine available to the NMDA receptor and, when blocked, may provide a

GABAergic signaling

Postmortem and imaging studies of people with schizophrenia have identified abnormalities in GABA neurotransmission that are associated with poor cognitive functioning. GABA_A receptors play an important part in mediating activity in the dorsolateral prefrontal cortex (DLPFC), which is critical for working memory [17]. GABA production is controlled by the enzyme GAD67 (a 67-kD isoform of glutamic acid decarboxylase), the expression of which is decreased in parvalbumin (PV)-expressing neurons,

Cholinergic signaling

The cholinergic system has also gained attention as a potential target for treating negative and cognitive symptoms. This is because cholinergic neurons innervate anatomical structures implicated in schizophrenia and participate in processes that are altered in patients such as attention, working memory, and motivated behaviors [23]. Relevant cholinergic nuclei are found in the (i) nucleus basalis of Meynert and medial septum (which innervate the prefrontal cortex and hippocampus,

Genetics and animal models

Like other common diseases, schizophrenia is multifactorial, with contributions from multiple susceptibility genes in conjunction with epigenetic, stochastic, and environmental factors [36]. Numerous studies in families, twins and adopted children have shown that genetic factors play a major role in the development of schizophrenia—a monozygotic twin of a person diagnosed with schizophrenia has a ∼50% likelihood to develop the disorder, as opposed to the ∼1% prevalence in the general population

The 22q11 deletion syndrome (22q11DS) and schizophrenia candidate genes

The 22q11DS (Figure 4) is a congenital malformation syndrome, which occurs in one of every 2000–4000 births and is caused by 22q11.2 microdeletions [47]. It has been estimated that ∼25–30% of all children with 22q11.2 microdeletions go on to develop schizophrenia [48]. Conversely, 22q11.2 microdeletions account for up to 1–2% of non-familial (sporadic) cases of schizophrenia 49, 50. To date, the bidirectional association for this CNV has not been demonstrated for any other chromosomal locus or

Neuregulin 1/ErbB4

More than 80 SNPS within the NRG1/ErbB4 receptor/ligand pair (Figure 5) have been associated with schizophrenia [43]. Although this association has been negative in some studies, there are multiple reports of NRG1 association with endophenotypes in patients: decreased PPI [68], reduced integrity of the white matter 69, 70, hypofrontality, age of onset of psychosis, and premorbid IQ [71]. The gene produces multiple isoforms through alternate promoters and splicing [72]. Most

DISC1

DISC1 (Figure 6) is a gene locus originally identified in a Scottish family, many of whom carried a balanced translocation between chromosomes 1 and 11 [81]. Of 37 individuals with this translocation, 29 had a psychiatric diagnosis, including schizophrenia (7 patients), bipolar disorder (1), and recurrent major depression (10). Linkage and association studies have also supported a role for the DISC1 locus in schizophrenia [82]. Recent studies have shown abnormalities in the expression of DISC1

Akt1/GSK-3

Akt is a protein kinase involved in various cellular functions, including metabolism, cell stress, and cell-cycle regulation. Akt also plays a part in regulating the size, survival and possibly the synaptic plasticity of neurons 93, 94, 95. Three isoforms of Akt have been identified (Akt1, Akt2 and Akt3) [96], but Akt1 has been the primary focus in almost all studies examining roles for Akt in schizophrenia. Akt1 haplotypes co-segregate with schizophrenia, suggesting that the AKT1 gene may be a

Conclusion

The criteria for the diagnosis of schizophrenia have evolved to classify patients with shared symptoms and course of illness. The general effectiveness of D₂ receptor antagonists in ameliorating psychosis suggested the possibility of a common pathobiology. However, current antipsychotic agents have multiple side effects with the potential to induce profound morbidity, and are ineffective in treating cognitive deficits and negative symptoms. The complex genetics of the syndrome we call

Acknowledgments

The co-first authors (CSK, JSB, NMB, ZF, RRG, JLO and SM) are supported by NIMH Schizophrenia Training Grant T32 MH018870. This work was also supported in part by a NARSAD Young Investigator Award (NMB), by NIH grants DA022413 and MH54137 (JAJ), and by the Lieber Center for Schizophrenia Research and Treatment.

References (107)

D.A. Lewis et al.
Catching up on schizophrenia: natural history and neurobiology
Neuron
(2000)
O.D. Howes et al.
The dopamine hypothesis of schizophrenia: version III--the final common pathway
Schizophr. Bull.
(2009)
A. Carlsson
The current status of the dopamine hypothesis of schizophrenia
Neuropsychopharmacology
(1988)
R.E. Steinpreis
The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis
Behav. Brain Res.
(1996)
R.W. Buchanan
The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments
Am. J. Psychiatry
(2007)
D.C. Javitt
Glycine transport inhibitors and the treatment of schizophrenia
Biol. Psychiatry
(2008)
H.Y. Lane
Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study
Biol. Psychiatry
(2008)
B. Moghaddam et al.
Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats
Science
(1998)
B. Moghaddam
Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia
Psychopharmacology
(2004)
J.H. Krystal
Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects
Psychopharmacology (Berl.)
(2005)

S.T. Patil

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial

Nat. Med.

(2007)

G.G. Kinney

Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents

J. Pharmacol. Exp. Ther.

(2003)

P.J. Conn

Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia

Trends Pharmacol. Sci.

(2009)

G.G. Kinney

A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models

J. Pharmacol. Exp. Ther.

(2005)

C. Schlumberger

Comparison of the mGlu(5) receptor positive allosteric modulator ADX47273 and the mGlu(2/3) receptor agonist LY354740 in tests for antipsychotic-like activity

Eur. J. Pharmacol.

(2009)

R. Galici

Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice

J. Pharmacol. Exp. Ther.

(2006)

S.G. Rao

Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory

J. Neurosci.

(2000)

T. Hashimoto

Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia

J. Neurosci.

(2003)

D.A. Lewis et al.

Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations

Arch. Neurol.

(2006)

D.A. Lewis

Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia

Am. J. Psychiatry

(2008)

Buchanan, R.W. (2009) MK0777 for the treatment of cognitive impairements in people with schizophrenia. Am. Coll....

K. Fejgin

Prefrontal GABA(B) receptor activation attenuates phencyclidine-induced impairments of prepulse inhibition: involvement of nitric oxide

Neuropsychopharmacology

(2009)

J.A. Berman

Cholinergic circuits and signaling in the pathophysiology of schizophrenia

Int. Rev. Neurobiol.

(2007)

A. Mobascher et al.

The molecular and cellular neurobiology of nicotine abuse in schizophrenia

Pharmacopsychiatry

(2008)

E.L. Ochoa et al.

Cognitive deficits in schizophrenia: focus on neuronal nicotinic acetylcholine receptors and smoking

Cell Mol. Neurobiol.

(2007)

T.J. Raedler

Towards a muscarinic hypothesis of schizophrenia

Mol. Psychiatry

(2007)

S. Sydserff

Selective alpha7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes

Biochem. Pharmacol.

(2009)

R. Freedman

Initial phase 2 trial of a nicotinic agonist in schizophrenia

Am. J. Psychiatry.

(2008)

R.C. Smith

Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder

Schizophr. Res.

(2009)

FDA (2009) Information for Healthcare Professionals: Varenicline (marketed as Chantix) and Bupropion (marketed as...

M.K. Popkin

Exacerbation of recurrent depression as a result of treatment with varenicline

Am. J. Psychiatry

(2008)

R. Freedman

Exacerbation of schizophrenia by varenicline

Am. J. Psychiatry

(2007)

E. Scarr et al.

Muscarinic receptors: do they have a role in the pathology and treatment of schizophrenia?

J. Neurochem.

(2008)

A. Shekhar

Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia

Am. J. Psychiatry

(2008)

PDSP NIMH Psychoactive Drug Screening Program: Ki Database,...

M. Karayiorgou et al.

Dissecting the genetic complexity of schizophrenia

Mol. Psychiatry

(1997)

Y. Ayhan

Animal models of gene-environment interactions in schizophrenia

Behav. Brain Res.

(2009)

M.S. Keshavan

Schizophrenia, “just the facts”: what we know in 2008 part 3: neurobiology

Schizophr. Res.

(2008)

K.K. Nicodemus

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

Mol. Psychiatry

(2008)

M.C. Clarke

The role of obstetric events in schizophrenia

Schizophr. Bull.

(2006)

N.C. Allen

Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database

Nat. Genet.

(2008)

P. Jia

SZGR: a comprehensive schizophrenia gene resource

Mol. Psychiatry

(2010)

J. Sebat

Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders

Trends Genet.

(2009)

B.A. Ellenbroek et al.

Animal models for the negative symptoms of schizophrenia

Behav. Pharmacol.

(2000)

C. Kellendonk

Modeling cognitive endophenotypes of schizophrenia in mice

Trends Neurosci.

(2009)

I.I. Gottesman et al.

The endophenotype concept in psychiatry: etymology and strategic intentions

Am. J. Psychiatry

(2003)

M. Karayiorgou

22q11.2 microdeletions: linking DNA structural variation to brain dysfnction and schizophrenia

Nat. Rev. Neurosci.

(2010)

M. Karayiorgou et al.

The molecular genetics of the 22q11-associated schizophrenia

Brain Res.

(2004)

V.K. Lasseter

Follow-up report of potential linkage for schizophrenia on chromosome 22q: part 3

Am. J. Med. Genet.

(1995)

B. Xu

Strong association of de novo copy number mutations with sporadic schizophrenia

Nat. Genet.

(2008)

Cited by (137)

Functionally selective and biased agonists of muscarinic receptors
2021, Pharmacological Research
Disruption of cholinergic signalling via muscarinic receptors is associated with various pathologies, like Alzheimer’s disease or schizophrenia. Selective muscarinic agonists possess therapeutic potential in the treatment of diabetes, pain or Sjögren's syndrome. The orthosteric binding site of all subtypes of the muscarinic receptor is structurally identical, making the development of affinity-based selective agonists virtually impossible. Some agonists, however, are functionally selective; they activate only a subset of receptors or signalling pathways. Others may stabilise specific conformations of the receptor leading to non-uniform modulation of individual signalling pathways (biased agonists). Functionally selective and biased agonists represent a promising approach for selective activation of individual subtypes of muscarinic receptors. In this work we review chemical structures, receptor binding and agonist-specific conformations of currently known functionally selective and biased muscarinic agonists in the context of their intricate intracellular signalling. Further, we take a perspective on the possible use of biased agonists for tissue and organ-specific activation of muscarinic receptors.
Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: focus on biological pathways and epigenetic mechanisms
2020, Neuroscience and Biobehavioral Reviews
When considering neurodevelopmental disorders (NDDs), Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) are considered to be among the most severe in term of prevalence, morbidity and impact on the society.
Similar features and overlapping symptoms have been observed at multiple levels, suggesting common pathophysiological bases. Indeed, recent genome-wide association studies (GWAS) and epidemiological data report shared vulnerability genes and environmental triggers across the two disorders. In this review, we will discuss the possible biological mechanisms, including glutamatergic and GABAergic neurotransmissions, inflammatory signals and oxidative stress related systems, which are targeted by adverse environmental exposures and that have been associated with the development of SZ and ASD. We will also discuss the emerging role of the gut microbiome as possible interplay between environment, immune system and brain development. Finally, we will describe the involvement of epigenetic mechanisms in the maintenance of long-lasting effects of adverse environments early in life. This will allow us to better understand the pathophysiology of these NDDs, and also to identify novel targets for future treatment strategies.
Neurobehavioral changes arising from early life dopamine signaling perturbations
2020, Neurochemistry International
Dopamine (DA) signaling is critical to the modulation of multiple brain functions including locomotion, reinforcement, attention and cognition. The literature provides strong evidence that altered DA availability and actions can impact normal neurodevelopment, with both early and enduring consequences on anatomy, physiology and behavior. An appreciation for the developmental contributions of DA signaling to brain development is needed to guide efforts to preclude and remedy neurobehavioral disorders, such as attention-deficit/hyperactivity disorder, addiction, bipolar disorder, schizophrenia and autism spectrum disorder, each of which exhibits links to DA via genetic, cellular and/or pharmacological findings. In this review, we highlight research pursued in preclinical models that use genetic and pharmacological approaches to manipulate DA signaling at sensitive developmental stages, leading to changes at molecular, circuit and/or behavioral levels. We discuss how these alterations can be aligned with traits displayed by neuropsychiatric diseases. Lastly, we review human studies that evaluate contributions of developmental perturbations of DA systems to increased risk for neuropsychiatric disorders.
Translating preclinical findings in clinically relevant new antipsychotic targets: focus on the glutamatergic postsynaptic density. Implications for treatment resistant schizophrenia
2019, Neuroscience and Biobehavioral Reviews
There is a growing interest in new molecular targets for antipsychotic therapy. Multiple signal transduction systems have been recently implicated in the pathophysiology of schizophrenia. However, the weight of each specific mechanism remains controversial. A need for a more vigorous approach to the pharmacotherapy of schizophrenia arises from the bedside: about 30–40% of patients do not respond to antipsychotic therapy.
Postsynaptic Density (PSD) proteins have recently attracted attention for their role in signal transduction modulation and for their potential implication in psychosis and cognition. The involvement of PSD in the pathophysiology of schizophrenia is supported by post mortem studies, preclinical animal models, modulation by antipsychotics, and association of PSD genes with schizophrenia in GWAS.
Taken together, these studies underline the role of PSD modulation, its effects on striatal function and its relationship with motor, executive- and cognitive-like functions suggesting a potential role of PSD proteins as a l target of novel intervention in the treatment of refractory psychosis.
Review: Genes Involved in Mitochondrial Physiology Within 22q11.2 Deleted Region and Their Relevance to Schizophrenia
2023, Schizophrenia Bulletin
Therapeutic potential of NOX inhibitors in neuropsychiatric disorders
2023, Psychopharmacology

View all citing articles on Scopus

^*: These authors contributed equally.

View full text

Trends in Pharmacological Sciences

ReviewSignaling pathways in schizophrenia: emerging targets and therapeutic strategies

Section snippets

Schizophrenia, signaling and drug development

Glutamatergic signaling

GABAergic signaling

Cholinergic signaling

Genetics and animal models

The 22q11 deletion syndrome (22q11DS) and schizophrenia candidate genes

Neuregulin 1/ErbB4

DISC1

Akt1/GSK-3

Conclusion

Acknowledgments

Catching up on schizophrenia: natural history and neurobiology

Neuron

The dopamine hypothesis of schizophrenia: version III--the final common pathway

Schizophr. Bull.

The current status of the dopamine hypothesis of schizophrenia

Neuropsychopharmacology

The behavioral and neurochemical effects of phencyclidine in humans and animals: some implications for modeling psychosis

Behav. Brain Res.

The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments

Am. J. Psychiatry

Glycine transport inhibitors and the treatment of schizophrenia

Biol. Psychiatry

Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study

Biol. Psychiatry

Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats

Science

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia

Psychopharmacology

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

Psychopharmacology (Berl.)

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial

Nat. Med.

Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents

J. Pharmacol. Exp. Ther.

Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia

Trends Pharmacol. Sci.

A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models

J. Pharmacol. Exp. Ther.

Comparison of the mGlu(5) receptor positive allosteric modulator ADX47273 and the mGlu(2/3) receptor agonist LY354740 in tests for antipsychotic-like activity

Eur. J. Pharmacol.

Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice

J. Pharmacol. Exp. Ther.

Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory

J. Neurosci.

Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia

J. Neurosci.

Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations

Arch. Neurol.

Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia

Am. J. Psychiatry

Prefrontal GABA(B) receptor activation attenuates phencyclidine-induced impairments of prepulse inhibition: involvement of nitric oxide

Neuropsychopharmacology

Cholinergic circuits and signaling in the pathophysiology of schizophrenia

Int. Rev. Neurobiol.

The molecular and cellular neurobiology of nicotine abuse in schizophrenia

Pharmacopsychiatry

Cognitive deficits in schizophrenia: focus on neuronal nicotinic acetylcholine receptors and smoking

Cell Mol. Neurobiol.

Towards a muscarinic hypothesis of schizophrenia

Mol. Psychiatry

Selective alpha7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes

Biochem. Pharmacol.

Initial phase 2 trial of a nicotinic agonist in schizophrenia

Am. J. Psychiatry.

Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder

Schizophr. Res.

Exacerbation of recurrent depression as a result of treatment with varenicline

Am. J. Psychiatry

Exacerbation of schizophrenia by varenicline

Am. J. Psychiatry

Muscarinic receptors: do they have a role in the pathology and treatment of schizophrenia?

J. Neurochem.

Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia

Am. J. Psychiatry

Dissecting the genetic complexity of schizophrenia

Mol. Psychiatry

Review
Signaling pathways in schizophrenia: emerging targets and therapeutic strategies