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Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010 May 28 ; 141(5):775-85. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Christopher Pittenger
Submitted 18 June 2010
Posted 22 June 2010
  I recommend the Primary Papers

The recent study from the Capecchi laboratory, in which the excessive grooming phenotype observed in HoxB8 knockout mice (Greer and Capecchi, 2002) was found to be mediated by the absence of HoxB8 in hematopoietically derived cells rather than in neurons, represents a startling and important advance. It comes as a surprise to many in the community—certainly to me—that a phenotype as specific and ethologically relevant as syntactic grooming would be modifiable by a specific alteration in microglia. And yet this is precisely what the new paper shows—and shows with very elegantly designed and performed experiments, which leave little doubt as to the striking conclusion. This study will increase interest in the interaction between immune or inflammatory processes and specific behaviors in a variety of basic and pathological contexts, and this is a salubrious advance in the field.

More vexing is the question of whether or not these mice in general, and the new finding in particular, advance our understanding of any specific neuropsychiatric condition. The mice have been described, in the title of the original paper and in numerous contexts since, as a potential mouse model of obsessive-compulsive disorder (OCD). This is a provocative assertion, and it requires careful consideration.

Certainly the idea of a deep connection between an aberrant immune response in the brain and the symptoms of OCD is not a new one. P.A.N.D.A.S. (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus) is a pediatric syndrome (still somewhat controversial) in which symptoms of OCD begin rather suddenly after a streptococcal infection in a susceptible child and then follow an episodic course, with exacerbations triggered by subsequent infections (Swedo et al., 1998). Localized brain inflammation triggered by autoantibodies, analogous to rheumatic fever and Sydenham’s chorea, represents the hypothesized causal link. Some authors have suggested that such an autoimmune pathogenesis may also be at play in adult OCD and not just in a small subset of pediatric-onset disease (e.g., Bhattacharyya et al., 2009). The new HoxB8 study, which produces a compulsive behavior through unclear actions (or lack of action) by HoxB8-deficient microglia, is quite different from such an autoantibody-mediated pathogenesis, but it resonates with the hypothesized connection between dysregulation of the immune system and OCD symptomatology.

However, the connection to OCD is based on an intuitive resemblance of the observed excessive grooming to repetitive and inflexible behaviors seen in OCD—that is, to the “face validity” of the model. Face validity can be a fickle guide in models of psychiatric disease. For example, excessive grooming has been described as OCD-like in other contexts (e.g., Welch et al., 2007), but it could as easily be interpreted as a model of trichotillomania, autistic stereotypy, Tourette syndrome, amphetamine-induced stereotypy, drug habit, or something ethologically unique to mice. Grooming is a particularly difficult phenotype to interpret in a cross-species comparison as it is quite variable among species—rodent grooming is quite different from primate grooming—and presumably subject to substantial selective pressure, due both to ecological and social factors (not to mention the presence or absence of fur). Therefore, the mere fact that the animals groom excessively is a slim basis for describing them as a model of OCD.

Recent studies have tried to extend the face validity of similar proposed models in other genetically modified mice by examining anxiety. For example, anxiety along with excessive grooming is seen in mice with a mutation in SAPAP3 (Welch et al., 2007) or with SliTrk5 (Shmelkov et al., 2010). Since OCD is categorized in DSM-IV as an anxiety disorder and often presents with significant anxiety (although not always, in my experience), this additional phenotype strengthens the face validity of the model. Even so, such face-validity comparisons are best considered as analogies to human conditions. It is far from clear that observable measures of anxiety in a mouse adequately parallel the psychic and cognitive type of anxiety experienced by patients with OCD. Furthermore, anxiety is an extraordinarily non-specific psychiatric symptom—I often ask residents, as an exercise, to name psychiatric disorders that are not frequently characterized by anxiety, and they are hard pressed to come up with more than a handful.

An additional evaluation uses predictive validity—that is, the ability of medications used to treat OCD to ameliorate the observed phenotypes. This was done in the studies of both the SAPAP3 and SliTrk5 mice, referenced above, in which SSRIs were found to ameliorate both excessive grooming and anxiety phenotypes. Such a predictive validity test also has significant weaknesses, however, because of the imprecise nature of both psychiatric diagnosis and psychiatric pharmacotherapy. SSRIs are of benefit in only 50-60 percent of cases of OCD, even with optimal dosing (see, e.g., Bloch et al., 2009). And SSRIs are also used to treat depression, generalized anxiety disorder, social anxiety disorder, premenstrual dysphoric disorder, post-traumatic stress disorder, bulimia, anorexia, and a host of other conditions. Therefore, response to an SSRI does not validate a mouse model as recapitulating core aspects of the neurobiology of OCD, and lack of response should not be interpreted as particularly undermining of a model’s validity.

Ultimately, the most valid models of OCD, or of any other neuropsychiatric condition, will be those based on confirmed aspects of the neurobiology of the disorder, such as well-validated genes of large effect size, specific molecular or cellular changes strongly and specifically associated with the disorder, or environmental stressors or insults with a similarly specific association. Such toe-holds into the pathophysiology of the disorder can be leveraged by carrying them over to animal models in which their downstream consequences, and potential ameliorative therapies, can be examined. Obviously, such validated hints of the pathophysiology of disease are few and far between in neuropsychiatric conditions, and virtually absent in obsessive-compulsive disorder, a relatively under-studied condition. In my view, until we have such biological grounding on which to base the construct validity of our models, it is best not to describe these or any other mice as representing “an animal model of OCD.” It is better to speak of an animal that exhibits excessive grooming, plain and simple. The relationship to OCD, or any other human neuropsychiatric condition, remains an empiric question that will be challenging to answer in a satisfying way.

However, this comment does not detract in any scientifically important way from the importance of the recent paper from the Capecchi group. They have certainly provided a valuable examination of an animal that exhibits maladaptively excessive and inflexible grooming. In addition, their striking finding of the critical role of microglia in producing this phenotype is of profound importance and will push the field towards a deeper appreciation of the importance of immune-brain interactions, not only for general brain health, but for the development and modulation of specific phenotypes. This is an exciting finding indeed.

References:

Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in mice. Neuron . 2002 Jan 3 ; 33(1):23-34. Abstract

Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry . 1998 Feb 1 ; 155(2):264-71. Abstract

Bhattacharyya S, Khanna S, Chakrabarty K, Mahadevan A, Christopher R, Shankar SK. Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive-compulsive disorder. Neuropsychopharmacology . 2009 Nov 1 ; 34(12):2489-96. Abstract

Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding JD, Feliciano C, Chen M, Adams JP, Luo J, Dudek SM, Weinberg RJ, Calakos N, Wetsel WC, Feng G. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature . 2007 Aug 23 ; 448(7156):894-900. Abstract

Shmelkov SV, Hormigo A, Jing D, Proenca CC, Bath KG, Milde T, Shmelkov E, Kushner JS, Baljevic M, Dincheva I, Murphy AJ, Valenzuela DM, Gale NW, Yancopoulos GD, Ninan I, Lee FS, Rafii S. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nat Med . 2010 May 1 ; 16(5):598-602, 1p following 602. Abstract

Bloch MH, McGuire J, Landeros-Weisenberger A, Leckman JF, Pittenger C. Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder. Mol Psychiatry . 2009 May 26. Abstract

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