Neurobiology of obsessive–compulsive disorder: insights into neural circuitry dysfunction through mouse genetics

doi:10.1016/j.conb.2011.04.010

Current Opinion in Neurobiology

Volume 21, Issue 6, December 2011, Pages 842-848

https://doi.org/10.1016/j.conb.2011.04.010 Get rights and content

The precise causal factors for obsessive–compulsive disorder (OCD) are not known, although, decades of research have honed in on the cortico-striatal-thalamo-cortical (CSTC) circuitry in the brain as a critical pathway involved in obsessions and the intimately linked compulsive–repetitive behaviors. Recent progress in human and mouse genetics have led to the identification of novel candidate susceptibility genes, which in turn have facilitated a more focused approach to unraveling the nature of circuitry dysfunction in OCD. The ability to perform invasive techniques in genetic animal models of OCD will be crucial for rapid advances in this field, and as such we review the most recent developments and highlight the importance of searching out common circuitry defects underlying compulsive–repetitive behaviors.

Highlights

► OCD is a prevalent neuropsychiatric disorder. ► Cortico-striatal-thalamo-cortical circuits are central to OCD core features. ► Several recently described genetic mouse models exhibit OCD-like behaviors. ► Genetic mouse models may help researchers identify common circuitry defects in OCD. ► Common circuitry defects may also help to explain key aspects of autism spectrum disorders.

Introduction

Despite the fact that the causes of OCD remain elusive, in recent years this disorder, once considered relatively obscure, has experienced a reemergence in the public consciousness. This is underscored by the creation of not one, but two separate reality/documentary-style television shows dedicated to this topic within the past two years (‘OCD Project’ which aired on VH1 and ‘Obsessed’ which aired on A&E). Perhaps this is the result of a growing acceptance that OCD is not obscure, but rather, ranks among the most prevalent neuropsychiatric disorders such as major depression, schizophrenia, and bipolar disorder.

It is estimated that the lifetime prevalence of OCD is 1–3% in the general population [1, 2], suggesting that within each of our social networks we may find family members, friends, or colleagues that live with this often debilitating condition. While there are several treatment options currently available [3, 4], the stark reality is that there remains a significant percentage of OCD sufferers that are either non-responsive or only partially responsive to the available treatment paradigms. Furthermore, last-resort invasive procedures such as deep brain stimulation or surgical procedures have had mixed success in alleviating severe symptoms [5], and thus these options remain an empirical art that is far from being mastered. This highlights the importance of continued research into the precise causes of OCD and continued exploration of novel targets that have promise to one day bring relief to all in need.

Section snippets

Theoretical framework for circuitry dysfunction in OCD

Diverse functional brain imaging technologies have allowed researchers to delve deep into the brains of OCD patients to seek out aberrations in neural circuits that control behavior. Over the past 25 years these non-invasive imaging approaches have consistently identified abnormal patterns of activity in a particular circuit, the CSTC loop [6^••] (Figure 1), and these studies have been highly influential in synthesizing the modern views on the neurobiology of OCD. Perhaps equally important over

Sapap3 null mice

SAP90/PSD95-associated protein 3 (SAPAP3) belongs to a family of four homologous genes encoding SAPAP proteins that are widely yet differentially expressed in the nervous system [17]. SAPAP3 is localized to the postsynaptic density (PSD) at excitatory synapses and is the only family member strongly expressed in the striatum. Genetic deletion of Sapap3 in mice caused behavioral abnormalities consisting of increased anxiety and compulsive self-grooming to the point of facial hair loss and skin

In search of a common neural circuitry defect

Despite the varying degrees to which each genetic mouse model recapitulates core aspects of the human condition of OCD, some notable commonalities have emerged. First, no single model is sufficient to recapitulate the entirety of the human condition of OCD. This is especially true given that the presence and content of obsessional thinking that is intimately tied to compulsive behavior is perhaps impossible to assess in a mouse [12]. Thus, it is important to focus on robust and easily

Conclusions and future perspectives

Searching out common circuitry defects in genetic animal models of OCD and various other disorders with overlap in the domain of compulsive–repetitive behaviors represents one of the most promising directions for future research in this field. In this respect it is important to urge inclusive (yet with tempered skepticism) as opposed to dismissive views concerning novel animal models. No animal model will adequately capture all aspects of a complex human disorder, yet significant aspects of

Conflict of interest

None declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We are grateful to Dr. Tanya Daigle for constructive comments on the manuscript. G.F. is supported by grants from the National Institutes of Health (NIMH R01MH081201), The Hartwell Foundation, Simons Foundation Autism Research Initiative (SFARI), Stanley Center for Psychiatric Research, and the SPARC program from Broad Institute of MIT and Harvard. J.T.T. would like to acknowledge support from NARSAD: The Brain and Behavior Research Fund (Young Investigator Award) and the NIMH (Ruth L.

References (44)

C. Pittenger et al.
Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive–compulsive disorder
NeuroRx
(2006)
S. Saxena et al.
Functional neuroimaging and the neuroanatomy of obsessive–compulsive disorder
Psychiatr Clin North Am
(2000)
J.J. Canales et al.
A measure of striatal function predicts motor stereotypy
Nat Neurosci
(2000)
L. Wang et al.
Assessing the validity of current mouse genetic models of obsessive–compulsive disorder
Behav Pharmacol
(2009)
J.M. Welch et al.
Differential mRNA expression and protein localization of the SAP90/PSD-95-associated proteins (SAPAPs) in the nervous system of the mouse
J Comp Neurol
(2004)
S. Zuchner et al.
Multiple rare SAPAP3 missense variants in trichotillomania and OCD
Mol Psychiatry
(2009)
O.J. Bienvenu et al.
Sapap3 and pathological grooming in humans: results from the OCD collaborative genetics study
Am J Med Genet B Neuropsychiatr Genet
(2009)
K. Aoyama et al.
Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse
Nat Neurosci
(2006)
Berman AE, Chan WY, Brennan AM, Reyes RC, Adler BL, Suh SW, Kauppinen TM, Edling Y, Swanson RA: N-acetylcysteine...
J.D. Rothstein et al.
Localization of neuronal and glial glutamate transporters
Neuron
(1994)

Y. Wang et al.

A screen of SLC1A1 for OCD-related alleles

Am J Med Genet B Neuropsychiatr Genet

(2009)

M.M. Weissman et al.

The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group

J Clin Psychiatry

(1994)

M. Karno et al.

The epidemiology of obsessive–compulsive disorder in five US communities

Arch Gen Psychiatry

(1988)

M.A. Jenike

Clinical practice. obsessive–compulsive disorder

N Engl J Med

(2004)

W.I. Haynes et al.

High-frequency stimulation of deep brain structures in obsessive–compulsive disorder: the search for a valid circuit

Eur J Neurosci

(2010)

G.E. Alexander et al.

Parallel organization of functionally segregated circuits linking basal ganglia and cortex

Annu Rev Neurosci

(1986)

R.L. Albin et al.

The functional anatomy of basal ganglia disorders

Trends Neurosci

(1989)

M.R. DeLong

Primate models of movement disorders of basal ganglia origin

Trends Neurosci

(1990)

C.R. Gerfen

The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia

Annu Rev Neurosci

(1992)

S. Korff et al.

Animal models of obsessive–compulsive disorder: rationale to understanding psychobiology and pharmacology

Psychiatr Clin North Am

(2006)

J.T. Ting et al.

Glutamatergic synaptic dysfunction and obsessive–compulsive disorder

Curr Chem Genomics

(2008)

D. Joel

Current animal models of obsessive compulsive disorder: a critical review

Prog Neuropsychopharmacol Biol Psychiatry

(2006)

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The interplay between environmental stress and genetic factors is thought to play an important role in the pathogenesis and maintenance of obsessive-compulsive disorder (OCD). However, the relative contribution of these causative antecedents in the manifestation of cognitive inflexibility—a phenotype often seen in obsessive-compulsive (OC)- spectrum disorders—is not fully understood.
In this study, we treated mice with 50 mg/L corticosterone (CORT, a glucocorticoid stress hormone) in their drinking water during adolescence. In adulthood, we assessed anxiety-like behaviour and locomotor activity; along with operant-based discrimination and reversal learning. RU-24969, a selective serotonin receptor 5-HT_1A/1B receptor agonist, was used as an acute pharmacological model of OC-like behaviour. RU-24969 (5 mg/kg) was administered prior to each reversal learning testing session.
We found that acute treatment with 5 mg/kg RU-24969 induced stereotyped hyperlocomotion in vehicle- and CORT-treated mice. Furthermore, pre-treatment with CORT in adolescence produced subtle anxiety-like behaviour in adult mice, and also resulted in an impairment to late-stage discrimination learning and alterations to reversal learning. Finally, acute treatment with 5 mg/kg RU-24969 caused an impairment to early-stage reversal learning.
Whilst we revealed dissociable detrimental effects of adolescent CORT treatment and acute 5-HT_1A/1B receptor agonism on discrimination and reversal learning, respectively, we did not find evidence of additive deleterious effects of these two treatments. We therefore suggest that while disrupted serotonergic signalling is likely to be involved in the cognitive phenotype of OC-spectrum disorders, distinct neuropathological pathways may be at play in mediating the role of stress as an antecedent in OCD and related illnesses.
Structural and functional brain imaging after treatment with selective-serotonin reuptake-inhibitors in obsessive-compulsive disorder: A mini review
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Obsessive-compulsive disorder (OCD) is a psychiatric disorder whose etiopathogenesis, according to various neuroimaging studies, seems to be linked to selective dysfunctions in regions within the cortico-striatal-thalamo-cortical circuit. Selective Serotonin Reuptake Inhibitors (SSRIs) are the first-line therapy for OCD but their neurobiological effects on the brain is only partially understood. Therefore, the aim of this review is to highlight structural and functional brain imaging modifications induced by SSRIs treatment.
A literature search on PubMed, Psych-Info and Embase database was performed. Studies including patients with OCD that analyzed the effect of SSRIs through structural and functional Magnetic Resonance Imaging were selected. Seven relevant studies were considered eligible for the present review.
Overall, the results of the reviewed studies showed that SSRIs treatment seems to normalize structural, in terms of the white matter and gray matter volumes, and functional activity alterations observed in OCD patients, especially in regions within the prefrontal cortex and striatum.
The poor design of the studies, the small and heterogeneous samples, differences in age, gender, illness course, comorbidities, treatment protocols and the different magnetic fields used make it difficult to generalize the results.
From the available evidence it emerged that SSRIs treatment has proven to be effective in normalizing brain structural and functional alterations observed in OCD patients. However, future neuroimaging investigations should focus on long-term effects of drugs on brain structure and function in OCD patients through longitudinal approaches in order to identify more effective treatments for these patients.
Pathway-specific alterations in striatal excitability and cholinergic modulation in a SAPAP3 mouse model of compulsive motor behavior
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Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this phenotype, the striatum efficiently adapts to pathological changes, often in ways that expand upon the original circuit impairment. Here, we show that SAPAP3 deletion causes non-synaptic and pathway-specific alterations in dorsolateral striatum circuit function. While somatic excitability was elevated in striatal projection neurons (SPNs), dendritic excitability was exclusively enhanced in direct pathway SPNs. Layered on top of this, cholinergic modulation was altered in opposing ways: striatal cholinergic interneuron density and evoked acetylcholine release were elevated, while basal muscarinic modulation of SPNs was reduced. These data describe how SAPAP3 deletion alters the striatal landscape upon which impaired corticostriatal inputs will act, offering a basis for how pathological synaptic integration and unbalanced striatal output underlying OCD-like behaviors may be shaped.
Acute administration of the NMDA receptor antagonists ketamine and MK-801 reveals dysregulation of glutamatergic signalling and sensorimotor gating in the Sapap3 knockout mouse model of compulsive-like behaviour
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Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours. Firstly, we investigated whether administration of the NMDA receptor (NMDAR) antagonist ketamine (30 mg/kg), would reduce anxiety and grooming behaviour in Sapap3 KO mice. Anxiety-like behaviour was measured via time spent in the light component of the light-dark box test. Grooming behaviour was recorded and scored in freely moving mice. In line with previous works conducted in older animals (i.e. typically between 6 and 9 months of age), we confirmed here that Sapap3 KO mice exhibit an anxious, compulsive grooming, hypolocomotive and reduced body weight phenotype even at a younger age (i.e., 2-3 months of age). However, we found that acute administration of ketamine did not cause a reduction in anxiety or grooming behaviour. We then investigated in vivo glutamatergic function via the administration of a different NMDAR antagonist, MK-801 (0.25 mg/kg), prior to locomotion and prepulse inhibition assays. We found evidence of altered functional NMDAR activity, as well as sexually dimorphic prepulse inhibition, a measure of sensorimotor gating, in Sapap3 KO mice. These results are suggestive of in vivo glutamatergic dysfunction and their functional consequences, enabling future research to further investigate novel treatments for OCD.
Striatal adenosine A<inf>2A</inf> receptor involvement in normal and large nest building deer mice: Perspectives on compulsivity and anxiety
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Obsessive-compulsive disorder (OCD) is characterized by recurring obsessive thoughts and repetitive behaviors that are often associated with anxiety and perturbations in cortico-striatal signaling. Given the suboptimal response of OCD to current serotonergic interventions, there is a need to better understand the psychobiological mechanisms that may underlie the disorder. In this regard, investigations into adenosinergic processes might be fruitful. Indeed, adenosine modulates both anxiety- and motor behavioral output. Thus, we aimed to explore the potential associations between compulsive-like large nest building (LNB) behavior in deer mice, anxiety and adenosinergic processes. From an initial pool of 120 adult deer mice, 34 normal nest building (NNB)- and 32 LNB-expressing mice of both sexes were selected and exposed to either a normal water (wCTRL) or vehicle control (vCTRL), lorazepam (LOR) or istradefylline (ISTRA) for 7- (LOR) or 28 days after which nesting assessment was repeated and animals screened for anxiety-like behavior in an anxiogenic open field. Mice were then euthanized, the striatal tissue removed on ice and the adenosine A_2A receptor expression quantified. Our findings indicate that NNB and LNB behavior are not distinctly associated with measures of generalized anxiety and that ISTRA-induced changes in nesting expression are dissociated from changes in anxiety scores. Further, data from this investigation show that nesting in deer mice is directly related to striatal adenosine signaling, and that LNB is founded upon a lower degree of adenosinergic A_2A stimulation.
Disruption of Astrocyte-Dependent Dopamine Control in the Developing Medial Prefrontal Cortex Leads to Excessive Grooming in Mice
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Astrocytes control synaptic activity by modulating perisynaptic concentrations of ions and neurotransmitters including dopamine (DA) and, as such, could be involved in the modulating aspects of mammalian behavior.
We produced a conditional deletion of the vesicular monoamine transporter 2 (VMAT2) specifically in astrocytes (aVMTA2cKO mice) and studied the effects of the lack of VMAT2 in prefrontal cortex (PFC) astrocytes on the regulation of DA levels, PFC circuit functions, and behavioral processes.
We found a significant reduction of medial PFC (mPFC) DA levels and excessive grooming and compulsive repetitive behaviors in aVMAT2cKO mice. The mice also developed a synaptic pathology, expressed through increased relative AMPA versus NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioral and synaptic phenotypes were rescued by re-expression of mPFC VMAT2 and L-DOPA treatment, showing that the deficits were driven by mPFC astrocytes that are critically involved in developmental DA homeostasis. By analyzing human tissue samples, we found that VMAT2 is expressed in human PFC astrocytes, corroborating the potential translational relevance of our observations in mice.
Our study shows that impairment of the astrocytic control of DA in the mPFC leads to symptoms resembling obsessive-compulsive spectrum disorders such as trichotillomania and has a profound impact on circuit function and behaviors.

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View full text

Neurobiology of obsessive–compulsive disorder: insights into neural circuitry dysfunction through mouse genetics

Highlights

Introduction

Section snippets

Theoretical framework for circuitry dysfunction in OCD

Sapap3 null mice

In search of a common neural circuitry defect

Conclusions and future perspectives

Conflict of interest

References and recommended reading

Acknowledgements

NeuroRx

Psychiatr Clin North Am

Nat Neurosci

Behav Pharmacol

J Comp Neurol

Mol Psychiatry

Am J Med Genet B Neuropsychiatr Genet

Nat Neurosci

Neuron

Am J Med Genet B Neuropsychiatr Genet

The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group

J Clin Psychiatry

The epidemiology of obsessive–compulsive disorder in five US communities

Arch Gen Psychiatry

Clinical practice. obsessive–compulsive disorder

N Engl J Med

High-frequency stimulation of deep brain structures in obsessive–compulsive disorder: the search for a valid circuit

Eur J Neurosci

Parallel organization of functionally segregated circuits linking basal ganglia and cortex

Annu Rev Neurosci

The functional anatomy of basal ganglia disorders

Trends Neurosci

Primate models of movement disorders of basal ganglia origin

Trends Neurosci

The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia

Annu Rev Neurosci

Animal models of obsessive–compulsive disorder: rationale to understanding psychobiology and pharmacology

Psychiatr Clin North Am

Glutamatergic synaptic dysfunction and obsessive–compulsive disorder

Curr Chem Genomics

Current animal models of obsessive compulsive disorder: a critical review

Prog Neuropsychopharmacol Biol Psychiatry