neuroimmune interactions are increasingly appreciated as both an important regulator of normal brain development and function and a potential contributor to the pathophysiology of a range of neuropsychiatric illnesses . in particular , there is accumulating evidence that immune dysregulation can contribute to obsessive - compulsive disorder ( ocd ) and tourette syndrome , at least in a subset of cases [ 1 , 2 ] .
ocd is characterized by unreasonable or excessive thoughts and fears ( obsessions ) and/or repetitive behaviors ( compulsions ) .
tourette syndrome , which is frequently comorbid with ocd , is characterized by tics : repetitive , stereotyped , involuntary movements and vocalizations [ 4 , 5 ] .
both ocd and tourette syndrome are accompanied by pathological changes in the corticobasal ganglia circuitry , especially in the striatum [ 6 , 7 ] . a role for dysregulated immune
function is particularly clear in the syndrome known as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections , or pandas .
pandas is characterized by the sudden onset of ocd and/or tic symptoms in childhood , following a streptococcal infection [ 9 , 10 ] .
the symptoms are usually dramatic and can include motor and vocal tics , obsessions , and compulsions .
it has been hypothesized that pandas arises from the development of brain - reactive autoantibodies after infection with group a streptococcus .
here we review the evidence for an immunological etiology for ocd , tourette syndrome , and related conditions .
we focus on one particular component of the immune system : microglia , the brain - resident immune cells .
these enigmatic cells have recently emerged as potential key players in the pathophysiology of neuropsychiatric disorders .
their activation in neurological disease has classically been associated with inflammation , neuronal damage , and neurodegeneration . however , over the past decade , novel roles for microglia in brain development , homeostasis , and plasticity have emerged .
a groundbreaking study demonstrated that microglia can engulf synapsis during normal postnatal development in mice .
synaptic pruning by microglia is necessary for the formation of brain circuitry and normal connectivity .
disruption of neuron - microglia interactions , through disruption of the fractalkine / fractalkine receptor signaling pathway , results in a range of neural and behavioral abnormalities .
microglia cells are also necessary for adult neurogenesis   and provide support for neuronal survival .
more recently , in keeping with our growing understanding of their roles in modulation of normal brain function , research has focused on neuropsychiatric conditions that are not characterized by frank neuronal death .
microglial contributions to pathophysiology in these disorders may be subtle and may relate to their noninflammatory functions . as new functions of microglia in normal brain development and function are discovered , and disruption of these functions in disease is characterized , new therapeutic strategies will emerge .
a number of animal models have been described in recent years in which the primary behavioral pathology is a maladaptive excess of repetitive behaviors , most commonly grooming .
these have often been interpreted as modeling ocd [ 1921 ] , but repetitive grooming has also been described in models of tourette syndrome , autism , rett syndrome , trichotillomania , and other conditions .
we first review several models in which the precise disease correlate is less firmly established but the association between microglial abnormalities in the corticostriatal circuitry is particularly striking .
animal studies with clearer etiopathogenic links to particular diseases are reviewed subsequently , together with the relevant clinical literature .
an early study reported that knockout of the hoxb8 gene produces compulsive grooming , progressing to hair removal and ultimately to skin lesions .
hoxb8 expression in the brain is restricted to microglia ( identified in these experiments by their expression of the cell - surface marker cd11b ) . strikingly , abnormal behavior in hoxb8 knockouts ( kos )
is rescued by transplantation of normal bone marrow , which repopulates the brain with wild - type microglia .
conversely , excessive grooming is produced by transplantation of bone marrow from hoxb8 ko mice into wild - type animals .
interestingly , not all cd11b cells in the brain express hoxb8 , which suggests that hoxb8 cells might be a subpopulation of microglia , constituting approximately 40% of total microglial cells . however , the total number of microglia cells in the brain of hoxb8 mutant mice is reduced by only 15% .
first , the hoxb8 subpopulation may be necessary for maintaining normal brain function , and loss of these cells in the ko animals may produce pathological grooming .
second , the population of hoxb8-negative microglia may expand in the knockout animals , which may lead to functional abnormalities .
in progranulin deficient ( grn ) mice , microglial activation leads to both excessive grooming and neurodegeneration .
this led to the suggestion that their repetitive behavior could be more related to classic inflammatory microglial activation and neuronal damage , rather than the loss of a neuroprotective or neuromodulatory function .
notably , autosomal dominant mutations in the human grn gene contribute to a common form of familial frontotemporal lobar degeneration [ 27 , 28 ] .
no association of grn mutations with ocd , tourette syndrome , or related conditions has been described .
cd11b cells in the brain are all of monocyte lineage , but they can be either resident brain microglia or peripherally derived monocytes . although both resident microglia and peripherally derived monocytes express the cx3cr1 [ 29 , 30 ] , only the latter express ccr2 , providing a powerful marker to discriminate between resident microglia and infiltrating monocyte in the brain .
cx3cr1 microglia are widely distributed through the brain parenchyma , while ccr2 monocytes are rarely seen in the healthy brain .
interestingly , microglia and monocytes play differential roles in neurodegeneration and brain injury [ 3133 ] . distinguishing between these two populations
may therefore prove to be quite important in understanding how microglial abnormalities can lead to repetitive behavioral pathology . in hoxb8 ko mice ,
the fact that abnormal behavior is rescued by transplanting in wild - type bone marrow   indicates that hoxb8 cells derived from circulating monocytes can enter the brain and have behavioral effects .
this is consistent with evidence indicating that hoxb8 regulates monocyte / macrophage differentiation from hematopoietic precursors [ 3436 ] . on the other hand
, another recent paper showed that mice lacking cx3cr1 , which is expressed by brain - resident microglia , show excessive grooming , along with other behavioral abnormalities that were interpreted as representing an autism - spectrum disorder - like phenotype .
considerable evidence suggests that immune dysregulation may contribute to the pathophysiology tourette syndrome [ 37 , 38 ] .
however , two recent studies , using different methodologies , have suggested abnormalities in microglial activation in patients with tourette syndrome . both studies focused on the basal ganglia . in a recent postmortem analysis of brains from tourette syndrome cases , lennington et al .   described increased number of cd45 microglial cells in the striatum .
these cells had morphological changes consistent with neurotoxic activation , concomitant with enriched expression of inflammatory genes [ 39 , 40 ] .
importantly , the brain samples were obtained from refractory adult patients ; no comparable postmortem data exist for more typical pediatric and/or fluctuating disease . a second recent study used in vivo positron emission tomography ( pet ) imaging with ( )
c-[r]-pk11195 ( pk ) , a ligand that binds to the transporter protein ( tspo ) , which is expressed by activated microglia . increased pk binding , indicative of inflammatory microglial activation , was observed in the caudate nuclei bilaterally in children with tourette syndrome .
an important caveat is that children with tourette syndrome were compared to adult healthy controls ( mean age 11.4 years versus mean age 28.7 years ) .
nevertheless , as the first study to image microglial activation in vivo in tourette syndrome , this is an important advance .
work in animal models of tic disorders may help to elucidate the role of microglia in their pathophysiology .
until recently , there have been no animal models of tourette syndrome with clear links to its etiopathophysiology in which to do such work .
recent work has identified a hypomorphic mutation in l - histidine decarboxylase ( hdc ) , which encodes the rate - limiting enzyme in the biosynthesis of histamine , as a rare but high - penetrance genetic cause of tourette syndrome .
knockout of the hdc gene , which recapitulates this molecular abnormality , thus produces an animal model with strong etiologic validity .
these mice exhibit behavioral and neurochemical abnormalities seen in patients with tourette syndrome , further confirming the validity of the model [ 44 , 45 ] .
we found that microglia cells are not activated in basal conditions in the striatum in hdc - ko mice ; rather , microglia from this mice exhibit reduced arborization and normal expression of inflammatory markers .
a similar effect is seen when neuronally derived histamine is specifically disrupted , through targeted virus - mediated ablation of histaminergic neurons in the posterior hypothalamus .
the total number of microglia is unchanged in ko animals , but the number of microglia expressing insulin - like growth factor 1 ( igf-1 ) is reduced .
igf-1 expressing microglia are necessary for neuronal survival and promote neurogenesis in nonpathological conditions [ 16 , 17 ] ; a specific reduction of these cells suggests impairment in these functions . inflammatory challenge with bacterial lipopolysaccharide ( lps )
dramatically changed this pattern : microglia activation in the striatum was enhanced in hdc - ko mice , compared with wild - type controls .
this was accompanied by enhanced induction of the proinflammatory cytokines il-1 and tnf-. taken together , these findings suggest that in this mouse model of tourette syndrome there is a deficit in microglia - mediated neuroprotection , accompanied by overreactivity to environmental challenge .
such complex mechanisms can not be appreciated in human studies and reinforce the importance of work in animal models to clarify the mechanisms of microglial dysregulation in neuropsychiatric disease .
the normal number of microglia in the hdc - ko model and their reduced arborization at baseline   contrast with the more numerous and activated microglia seen postmortem .
it is possible that the activation of microglia observed in patients with tourette syndrome emerges only after challenge by environmental factors , such as infection , or over the course of aging .
our studies in mice [ 44 , 46 ] are performed in a pathogen - free environment , in young adult mice .
after lps challenge , microglia activation in the animal model much more closely resembles that seen postmortem in humans .
regardless of this consideration , all the studies point to activation of microglia in the basal ganglia in tourette syndrome [ 39 , 41 , 46 ] , irrespective of the complexity of the underlying mechanisms .
, however , this evidence is much weaker than in the case of tourette syndrome , except in the case of pandas , to which we return below .
more particularly , the role of microglia cells in ocd has not been clearly elucidated .
the hoxb8 knockout mouse , described above [ 19 , 25 ] , has been described as a mouse model of ocd and may thus implicate microglial dysregulation in the disorder ; however , clear clinical data linking abnormalities in the hoxb8 gene , or the consequences of its disruption , to ocd has yet to emerge . to date , there are no imaging or postmortem studies describing microglia abnormalities in patients with ocd . obsessive - compulsive disorder ( ocd ) and tourette syndrome often strike in childhood . in a subset of cases ,
acute onset temporally coincides with a bout of infectious disease , particularly with streptococcus ; this clinical syndrome is known as pandas , or more generally pediatric acute - onset neuropsychiatric syndrome ( pans ) . by analogy with the better - understood pathophysiology of rheumatic fever and sydenham 's chorea , ocd and tourette syndrome symptoms in these cases
have been hypothesized to arise from the development of autoantibodies that cross - react with proteins normally expressed in the brain ; this mechanism is known as molecular mimicry . while many details of pandas as a clinical entity remain unclear , and some are controversial , the association of immune dysregulation with ocd and tourette syndrome symptoms in this subset of pediatric patients is increasingly clear .
the tspo / pk pet imaging study of microglial activation described above examined both noninfectious tourette syndrome and pandas .
children with pandas had increased pk binding in the striatum with respect to adult healthy controls ; this corresponds with increased striatal volumes previously described during acute illness in pandas patients [ 48 , 49 ] .
inflammation was higher and more broadly spread through the bilateral caudate and lentiform nucleus in pandas than in non - pandas tourette syndrome .
importantly , this comparison with age - matched patients avoids the interpretive difficulties created by comparison to an adult healthy control group ; the observed differences support the notion that pandas is etiologically distinct from non - pandas tourette syndrome .
a recent study in mice examined the effects of intranasal group a streptococcal ( gas ) infection and may begin to shed light on the role of microglia in pandas . repeated intranasal gas inoculations result in increasing the number of cd68/iba1 activated microglia in the glomerular layer of the olfactory bulb .
abnormal synaptic pruning , probably mediated by microglia , was also observed ( see below ) .
the majority of activated microglia were found in close proximity to cd4 t cells , suggesting that gas antigens could be presented to th17 cells by local microglia .
the role of microglia in neurodegenerative diseases has been understood in terms of classic , inflammatory activation , which may be both a consequence and a cause of neuronal damage . in ocd and tourette syndrome ,
which are not characterized by frank neural degeneration , the nature of any contribution of microglial dysregulation to pathophysiology is much less clear .
nave hdc - ko mice display morphological abnormalities in striatal microglia that suggest quiescence , normal expression of inflammatory markers , but a reduced number of igf-1 expressing microglia .
igf-1 expression by microglia is induced by th2 cytokines such as il-4 , which induce a neuroprotective phenotype , at least in organotypic hippocampal cultures . in vivo , igf-1 expressing microglia support cortical neurons during development and promote neurogenesis in the adulthood [ 16 , 17 , 52 ] . igf-1
thus , deficiency of igf-1 microglia in this animal model of tourette syndrome might lead to impaired neuroprotection and , consequently , to enhanced susceptibility to neuroinflammation after an environmental challenge ( figure 1 ) .
consistent with this , lps challenge triggers an exaggerated response in hdc - ko mice , both at the level of morphological activation and the production of the inflammatory cytokine il-1 ( figure 1 ) .
more generally , these results suggest that , in some neuropsychiatric disorders in which no marked neurodegeneration occurs , microglial dysregulation may constitute a failure of neuroprotective functions , which may create a vulnerability to neuroinflammation .
this mechanism may explain observations in other animal studies , in which loss of microglia - specific genes triggers abnormal grooming behavior [ 15 , 25 ] .
for example , cx3cr1 is a key molecule for neuron - glia communication and has a role in neuroprotection [ 5557 ] , which supports the interpretation that knocking it out disrupts neuroprotective or regulatory functions of microglia ( figure 1 ) . in postmortem tourette 's samples ,
loss of certain types of interneurons has been reported in the basal ganglia [ 39 , 58 , 59 ] .
we have found reduced igf-1 expressing microglia in the striatum in the hdc - ko model of tourette syndrome pathophysiology .
these igf-1 microglial cells are required for neuronal support during postnatal development , at least in the cortex [ 16 , 17 , 52 ] .
although these phenomena have not been linked , it is plausible that impaired igf-1 microglial function in the maintenance of striatal neurons might be causative of neuronal loss observed in tourette syndrome ( figure 2 ) .
hdc - ko mice have not been reported to develop spontaneous reduction of striatal interneurons ; however , this might happen in aging mice or young mice subjected to immune challenge .
in fact , hdc - ko microglia are more susceptible to lps - induced activation than wild - type microglia .
recent studies have described a key role for microglia in synaptic pruning during development , with long lasting consequences in adulthood [ 13 , 14 ] .
cx3cr1 knockout mice exhibit deficient synaptic pruning , excessive grooming , and social deficits . whether this function is altered in ocd ,
progranulin ko mice , on the other hand , have abnormal microglial activation and increased synaptic pruning , which results in elimination of inhibitory synapses in the ventral thalamus ( figure 2 ) , hyperexcitability in the thalamocortical circuits , and repetitive behavioral pathology . as mentioned above , there is limited but promising evidence from animal studies that synaptic pruning might be altered in pandas .
using an animal model of intranasal gas infection , dileepan and coworkers observed microglial activation and loss of vglut2 , a marker of excitatory synapses .
these results raise the possibility that synaptic pruning of excitatory connections may be increased in pandas ( figure 2 ) .
their contact instances with neuronal synapses are reduced in frequency by reductions in neuronal activity [ 61 , 62 ] . in the aging retina , for example
this may lead to impairments in their surveillance ability [ 63 , 64 ] . in the hdc - ko mouse ,
it is possible that microglial abnormalities in this animal model lead to alterations of synaptic pruning .
preliminary results suggest that hdc - ko animals may have cx3cr1 deficiencies ( frick et al .
cx3cr1 deficiency produces altered microglial morphology , similar to what is seen in hdc - ko mice . investigation of synaptic pruning in hdc - ko mice , and other mouse models of tourette syndrome , is warranted .
such interactions have , however , been described in rett syndrome , an autism - spectrum disorder characterized by mutation of the methyl - cpg - binding protein-2 gene ( mecp2 ) .
mecp - null microglia release dramatically higher levels of glutamate , and microglia - derived glutamate has neurotoxic effects on dendrites and synapses .
it is plausible that microglia - derived glutamate might similarly contribute to the pathophysiology of ocd ( figure 2 ) .
whether microglial abnormalities in ocd and tourette syndrome , or in any of the animal models described above , are associated with glutamate dysregulation is an important area for future study .
while evidence for microglial dysregulation in ocd , tourette syndrome , and pandas is growing , much remains unclear .
the case for microglial dysregulation is strongest in the case of tourette syndrome ; recent postmortem and pet imaging studies have produced convergent evidence for increased microglial activation in the striatum in patients [ 4042 ] .
this is complemented by our studies in the hdc - ko mouse model of tourette syndrome .
we have proposed that these mice capture a pathophysiologically important gene x environment interaction , in which deficiency in microglia - mediated neuroprotection produces a susceptibility to inflammatory changes upon environmental challenge .
this hypothesis needs to be explored in other well - validated models and in clinical contexts to test its generality .
mechanisms by which microglial abnormalities contribute to disease are likely to be shared across distinct etiologies and traditional diagnoses .
for instance , abnormal synaptic pruning was observed both in animals inoculated with gas ( which may capture key elements of the pathophysiology of pandas ) and in mice that develop excessive grooming after inactivation of the progranulin gene . in both cases , increased synaptic pruning cooccurs with microglia activation . in cx3cr1 knockout mice , deficient synaptic pruning accompanies alterations in neuron - microglial communication .
this is accompanied by social deficits , which has been interpreted as an autism - like phenotype .
results from these models must be interpreted cautiously , as neither progranulin nor cx3cr1 has been clearly associated with any of these conditions in humans . abnormal synaptic pruning by microglia in the more pathophysiologically grounded hdc - ko model of tourette syndrome is warranted .
these studies in animal models are intriguing and allow detailed mechanistic analysis , but their relevance for the understanding of clinical disease remains to be firmly established .
information about microglial abnormalities in patients with ocd , tourette syndrome , and pandas remains very limited .
this is a recently opened frontier in our understanding of the pathophysiology of these disorders .
it is , however , one of great promise , which may lead to the identification of novel therapeutic targets .
 there is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive - compulsive disorder ( ocd ) , tourette syndrome , and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections ( pandas ) . 
 the mechanistic details of this pathophysiology , however , remain unclear . here 
 we focus on one particular component of the immune system : microglia , the brain 's resident immune cells . 
 the role of microglia in neurodegenerative diseases has been understood in terms of classic , inflammatory activation , which may be both a consequence and a cause of neuronal damage . in ocd and tourette syndrome , which are not characterized by frank neural degeneration , the potential role of microglial dysregulation is much less clear . 
 here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in ocd , tourette syndrome , and pandas . 
 we also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology , beyond neuroinflammation , including failures in neuroprotection , lack of support for neuronal survival , and abnormalities in synaptic pruning . 
 recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues . 
1. Introduction
2. Possible Mechanisms
3. Conclusions and Future Directions