Infectious and Immune Factors in the Pathogenesis of Neurodevelopmental Disorders: Epidemiology, Hypotheses, and Animal Models

Home , Cell damage, Mady Hornig, Pyknosis

MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 7: 200–210 (2001)

INFECTIOUS AND IMMUNE FACTORS IN THE PATHOGENESIS OF NEURODEVELOPMENTAL DISORDERS:EPIDEMIOLOGY,HYPOTHESES, AND ANIMAL MODELS

Mady Hornig and W. Ian Lipkin* Emerging Diseases Laboratory, Gillespie Neuroscience Research Facility, University of California, Irvine, California

Both genetic and environmental factors contribute to the pathogen- Perinatal central nervous system (CNS) infection [Chess, esis of a wide variety of neurodevelopmental disorders, including autism, 1971; Gillberg and Gillberg, 1983; Hoon and Reiss, 1992; Barak mental retardation, and schizophrenia. Some heritable disorders approach 100% penetrance; nonetheless, even in these disorders, subtle aspects of et al., 1999] and disturbed neuroimmune networks [Warren et clinical disease expression may be influenced by the environment. In other al., 1986; 1987; 1990; 1991; 1994; 1995; Singh et al., 1991; disorders with genetic influences, exogenous factors, and the timepoint(s) 1993; 1997a,b; 1998; Singh, 1996; 1997; Burger and Warren, during nervous system development at which they are introduced, modu- 1998; Warren, 1998] have been proposed as factors in the late expression of disease. Elucidation of the mechanisms guiding this intri- cate interplay between host response genes, environmental agents, and the pathogenesis of autism spectrum disorders. An immune or in- neurodevelopmental context within which these interactions occur, is nec- fectious basis for autism is supported by epidemiologic studies essary to understand the continuum of clinical outcomes. This chapter will suggesting an increased rate of autism in particular geographic review the evidence that infectious and immune factors may contribute to regions [Gillberg et al., 1991; Baron-Cohen et al., 1999; De- the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify partment of Developmental Services, 1999; Gillberg and Wing, processes by which neural circuitry may be compromised, and outline areas 1999], season-of-birth effects [Bartlik, 1981; Kostantareas et al., for future research. © 2001 Wiley-Liss, Inc. 1986; Burd, 1988; Tanoue et al., 1988; Atlas, 1989; Gillberg, MRDD Research Reviews 2001;7:200–210. 1990; Bolton et al., 1992; Mouridsen et al., 1994; Barak et al., 1995; 1999; Ticher et al., 1996; Torrey et al., 1997; Stevens et Key Words: neurodevelopmental disorders; autism; virus; immune; Borna al., 2000], and linkage to viral and/or immune factors [Chess, disease virus; animal models 1971; Warren et al., 1986; 1987; 1990; 1991; 1994; 1995; Singh et al., 1991; 1993; 1997a,b; 1998; Singh, 1996; 1997; Burger and Warren, 1998; Warren, 1998; Stevens et al., 2000]. Heri- table predisposing factors may include immunologically relevant o established animal model for autism exists that ade- influences such as linkages to major histocompatibility complex quately addresses autism’s: 1) likely perinatal origins (MHC) genes [Warren et al., 1992; 1996a,b; Warren and Singh, N[Gillberg and Gillberg, 1983; Hoon and Reiss, 1992; 1996; Warren, 1998]; increased frequency of the null allele of Bauman and Kemper, 1994]; 2) linkage to viral and/or immune the complement component 4b locus, located in the MHC factors [Chess, 1971; Warren et al., 1986; Singh et al., 1991; complex [Warren et al., 1991]; and increased frequency of a 1993; 1997a,b; Singh, 1996; 1997; Warren, 1998]; 3) association family history of autoimmune disorders [Comi et al., 1999]. with hippocampal, amygdalar, and cerebellar dysfunction [Bau- Animal models and the epidemiology of autism, then, suggest man and Kemper, 1994]; 4) connection with dopamine and that genetic and environmental components work in concert to serotonin disturbances [Cook, 1990; Anderson, 1994; Cook and cause disease. Frustration with the ability to move beyond Leventhal, 1996; Cook et al., 1997]; and 5) wide spectrum of simple allelic associations to genetic causation has led to models neurobehavioral derangements (motor, postural, and sensory based on interactions of multiple genes, and reintroduction of deficits; hypotonia; stereotypies; poor eye contact; mental retar- the environment into the nature-nurture equation. Although dation; islands of normal to supernormal functioning) superim- controversial, reports that the rate of autism spectrum disorders posed on impairments in social interaction, communication, and behavior [Wing, 1997]. Additionally, although perinatal exposure to infectious agents and toxins is linked to the pathogenesis Grant sponsor: National Institutes of Health; Grant numbers: NS29425, MH57467, HD37546, MH01608; Grant sponsor: the MIND Institute of UC Davis; Grant of neuropsychiatric disorders, the mechanisms by which envi- sponsor: the CAN Foundation; Grant sponsor: the Tourette Syndrome Association. ronmental triggers interact with developing immune and neural *Correspondence to: W. Ian Lipkin or Mady Hornig, Emerging Diseases Laboratory, 3101 GNRF, University of California, Irvine, CA, 92697-4292. elements to create neurodevelopmental disturbances are poorly E-mail: [email protected], [email protected] understood.

© 2001 Wiley-Liss, Inc. may be increasing [Gillberg et al., 1991; tion. Alternatively, tissue damage and or a virally-triggered autoimmune dia- Department of Developmental Services, disease may be the indirect result of a thesis. Only limited conclusions may be 1999; Gillberg and Wing, 1999], and that host immune response to microbial gene drawn from these studies, as they are this increase is restricted to certain geo- products present in neural cells. Immune based on small, incompletely character- graphic regions [Baron-Cohen et al., responses to microbial agents can also ized, heterogeneous populations differing 1999; Department of Developmental lead to breakdown of tolerance to host in etiology and course, and often diag- Services, 1999; Gillberg and Wing, antigens and result in tissue damage nosed through superficial screening using 1999], provide further support for envi- [Zhao et al., 1998]. The agent responsi- Diagnostic and Statistical Manual (DSM) ronmental factors in the pathogenesis of ble for induction of autoimmunity need criteria alone, without use of standard- these disorders. not be present in CNS at the time of ized diagnostic instruments such as the These factors may include perinatal clinical presentation. Furthermore, the Autism Diagnostic Interview-Revised central nervous system (CNS) infection original infection may have been periph- (ADI-R) or Autism Diagnostic Observa- [Desmond et al., 1967; Chess, 1971; eral, as is the case in Sydenham’s chorea, tion Schedule (ADOS). Occasionally, Blattner, 1974; Peterson and Torrey, or as is proposed for tics and obsessions similar immune disturbances are noted in 1976; Chess, 1977; DeLong et al., 1981; following streptococcal infection. Yet first degree relatives or neurologic or Schwab, 1982; Gillberg and Gillberg, another mechanism for brain disease is healthy controls; however, in most stud- 1983; Markowitz, 1983; Ivarsson et al., persistent noncytopathic viral infection. ies, comparison groups are not screened 1990; Mason-Brothers et al., 1990; Ritvo Such infections can profoundly impact for presence of autism spectrum disorder et al., 1990; Gillberg and Coleman, 1992; neurotransmitter function or brain devel- symptoms or disorder. Controls for such Hoon and Reiss 1992; Tepper et al., opment, yet remain cryptic unless spe- factors are time of blood collection, se- 1998; Barak et al., 1999] and toxins cific reagents are used for detecting viral rum/plasma vs. intracellular sources of [Anonymous, 1999; Rice and Barone, gene products [Lipkin et al., 1988a,b; cytokines, medications, age, IQ, psycho- 2000; Weiss and Landrigan, 2000]. Oldstone 1989a,b,c]. Diverse neuropsy- social factors, immunization and infec- chiatric outcomes may even result from tious disease history, or family history of EVIDENCE TO SUPPORT A infection with a single agent, depending immune-based disorders. Findings of im- ROLE FOR VIRAL INFECTION on: 1) timing of infection relative to the mune disturbances in peripheral blood IN THE PATHOGENESIS OF status of neural or immune systems (in specimens have generally not been as- NEURODEVELOPMENTAL utero, juvenile, adult); 2) genetic context sessed or corroborated in cerebrospinal DISORDERS (e.g., MHC antigens determining im- fluid (CSF) samples and immune-medi- The implication of a role for pre- mune response and subsequent neuropa- ated mechanisms have not been defini- natal and/or postnatal viral infections in thology); and/or 3) other environmental tively supported by autopsy or brain im- the etiology of autism stems from retro- factors (infectious agents, toxins, psycho- aging studies. Nonetheless, although the spective epidemiologic studies of in utero social stress). degree of convergence of epidemiologic, or perinatal viral exposures, of seasonal Despite a finding of season-of- genetic, immunologic, and biochemical and geographic factors, and, more indi- birth effects in several studies [Bartlik, findings across or within subsets of chil- rectly, from studies of immune aberra- 1981; Burd, 1988; Gillberg, 1990; Barak dren with autism spectrum disorders is as tions in the blood of children with autism et al., 1995; 1999; Ticher et al., 1996; yet insufficient to warrant firm conclu- [Mason-Brothers et al., 1990; Gillberg Stevens et al., 2000]—many of which sions regarding pathogenesis, the data and Coleman, 1992; Delgiudice-Asch suggest a preponderance of March provide intriguing clues about potential and Hollander, 1997; Warren, 1998; and/or August births or a second trimes- mechanisms that may contribute to neu- Trottier et al., 1999]. A number of con- ter pathogen exposure amongst children ral injury. genital microbial exposures have been re- with autism—other studies have not Several reports are consistent with ported in association with autistic fea- confirmed this link [Landau et al., 1999]. diminished Th1 and increased Th2 re- tures, including rubella virus [Desmond Even if a microbial link is confirmed for sponses in autism: 1) mitogen-stimulated et al., 1967; Chess, 1971; Deykin and a subset of children with autism, other T cell proliferation is decreased in some MacMahon, 1979], cytomegalovirus factors may also vary seasonally, (e.g., [Stubbs and Crawford 1977; Warren et [Blattner, 1974; Stubbs and Crawford, nutritional differences) and influence ex- al., 1986], but not all [Ferrari et al., 1988] 1977; Markowitz, 1983; Stubbs et al., pression of disease [Gillberg and studies; 2) Th1 (IFN-␥ϩ CD4ϩ and 1984; Ivarsson et al., 1990; Ritvo et al., Coleman, 1992]. IL-2ϩ CD4ϩ cells) and TC1 (IFN-␥ ϩ 1990], herpes simplex virus [Peterson and Studies of immunologic function CD8ϩ and IL-2ϩ CD8ϩ cells) T cells are Torrey 1976; DeLong et al., 1981; Ritvo in children with autism reveal a wide reduced, and Th2 (IL-4ϩ CD4ϩ cells) et al., 1990], varicella zoster virus [Stubbs array of abnormalities, including de- and TC2 (IL-4ϩ CD8ϩ cells) T cells are and Crawford 1977; Deykin and Mac- creased cellular immune capacity [War- reportedly increased [Gupta et al., 1998]; Mahon, 1979], enteroviruses [Sells et al., ren et al., 1986; 1990; Wright et al., 3) natural killer cell activity is reduced 1975], human immunodeficiency virus 1990; Yonk et al., 1990; Denney et al., [Warren et al., 1987], despite unchanged [Tepper et al., 1998], and syphilis [Stubbs 1996]; decreased plasma complement numbers of natural killer cells [Warren et and Crawford, 1977; Schwab, 1982]. component C4b [Warren et al., 1994; al., 1990]; and 4) increased levels of se- Establishing a causal relationship 1995]; and increased humoral immune rum IgE [Gupta et al., 1996; Trottier et between infection with a microbial agent and autoantibody responses [Weizman et al., 1999]. Furthermore, as Th2 cells are and a specific brain disease can be com- al., 1982; Singh et al., 1993]. These ab- implicated in systemic (nonorgan spe- plex [Lipkin and Hornig, 1998]. In some normalities provide general support for cific) autoimmune disorders [De Carli et instances, for example, herpes simplex the hypothesis that children with autism al., 1994; Singh et al., 1999], the in- encephalitis, the agent is readily impli- may be predisposed to respond abnor- creased autoantibody production [Todd cated: the virus is present in brain and mally to viral infections either through and Ciaranello, 1985; Todd et al., 1988; destroys infected tissue through replica- the establishment of persistent infections Plioplys et al., 1989a,b; Yuwiler et al.,

MRDD RESEARCH REVIEWS ● PATHOGENESIS OF NEURODEVELOPMENTAL DISORDERS ● HORNIG AND LIPKIN 201 1992; Singh et al., 1993, 1997a,b; 1998; cules, but negative for IL-2 receptor or NEONATAL BORNAVIRUS Connolly et al., 1999] and family history CD25) in autism [Plioplys et al., 1994], INFECTION OF LEWIS RATS: of autoimmune disorders [Money et al., consistent with the pattern seen in several AN ENVIRONMENTAL MODEL 1971; Raiten and Massaro, 1986; Gill- autoimmune disorders [Burmester et al., OF NEURODEVELOPMENTAL berg et al., 1992; Comi et al., 1999] 1984; Hafler et al., 1985; Bergroth et al., DAMAGE reported for children with autism lend 1988], levels of DRϩ IL2Ϫ T cells in Borna disease virus, an atypical, further support to the idea that a Th2 children with autism are inversely corre- neurotropic, noncytolytic, negative- predominant immune response may play lated with plasma levels of C4b [Warren strand RNA virus, is tropic for limbic a role in autism pathogenesis. In contrast, et al., 1995]. The DR beta 1 gene is and cerebellar circuitry. Infection causes Singh reports increased plasma IL-12 and located in close proximity to the C4b a spectrum of behavioral deficits depend- IFN-␥ levels in autism [1996], findings gene on the HLA region of chromosome ing on the age, immune status, central more consistent with Th1 than Th2- 6, and is also near to genes encoding IgA nervous system maturity, and genetics of weighted responses. Lastly, a preliminary and 21-hydroxylase (class III region) the host. In immunocompetent adult report by Nelson and colleagues indicates [Wilton et al., 1985; Brai et al., 1994; Lewis rats, infection results in meningoencephalitis, diffuse central nervous sys- a lower level of autoantibodies to MBP, Fiore et al., 1995; Reil et al., 1997; Schr- tem damage, dopamine neurotransmitter GFAP, and NAFP at birth in children oeder et al., 1998]. IgA deficiency, also disturbances, and disorders of movement with autism or mental retardation than in noted in autism [Warren et al., 1997], is and behavior [Solbrig et al., 1994]. Neo- normal controls [Nelson et al., 2000]. associated with the presence of autoanti- natally infected Lewis rats have only min- These apparent inconsistencies in levels bodies [Brai et al., 1994; Fiore et al., imal, transient inflammation [Hornig et of autoantibodies in children with autism 1995] and an increased incidence of overt al., 1999] but nonetheless have abnor- might be explained by the difference in autoimmune disease [Barka et al., 1995]. malities of hippocampal and cerebellar time of sampling, with later timepoints Some DR beta 1 alleles reportedly have a development [Hornig et al., 1999], reflecting a break in immune tolerance. very strong association with autism growth [Bautista et al., 1994], play be- It is conceivable that there is a link [Warren et al., 1992; Daniels et al., 1995; havior [Pletnikov et al., 1999a], emo- between susceptibility to infection with Warren et al., 1996a, b], although one tional reactivity [Hornig et al., 1999], measles virus and HHV-6 and an auto- larger study of multiplex sibships with socioemotional communication (prelim- immune diathesis. The observation that autism did not confirm this result [Rog- inary data, Hornig and Lipkin), spatial the CD46 receptor binds complement ers et al., 1999]. Given the presumed and aversive learning, [Dittrich et al., proteins C3b and C4b is interesting in heterogeneity of the disorder, and the 1989], locomotor activity [Hornig et al., light of reports of decreased plasma levels possibility that genetic loading in families 1999; 2000], and taste preferences [Bau- of C4b [Warren et al., 1994; 1995] and with multiple affected members may be tista et al., 1994]. These abnormalities increases in the null allele of the C4b less likely to require exposure to an en- bear obvious similarities to the impaired gene [Warren et al., 1991] in autism. The vironmental factor (e.g., virus, bacteria, social interaction and atypical responses C4b gene is located in the MHC on toxin, or other agent) in order to lead to to sensory and emotional stimuli patho- chromosome 6; partial C4 deficiency and the autistic phenotype, the absence of gnomonic of autism. the C4b null allele are associated with an linkage in this one study does not rule Neonatal rat infection presents an increased susceptibility to a variety of au- out a role for an HLA-linked immuno- intriguing model for neuropsychiatric ill- toimmune diseases [Brai et al., 1994; Ul- genetic vulnerability in a subset of chil- ness; its immunopathologic correlates are giati and Abraham, 1996; Naves et al., dren with autism. Immunogenetic stud- more subtle and the cerebellar and hip- 1998; Kawano et al., 1999]. CD46 re- ies that compare subpopulations with and pocampal dysgenesis observed is consis- ceptor, in addition to serving as the entry without evidence of immune dysfunc- tent with the neurodevelopmental ab- site for vaccine strains of measles [Tatsuo tion will be required to address this pos- normalities reported in autism [Kemper et al., 2000], is also the entry site for sibility. and Bauman, 1993], schizophrenia [Alt- HHV-6 [Santoro et al., 1999; Clark, Expression of complex neuropsy- shuler et al., 1987; Fish et al., 1992], and 2000]. Increased levels of antibodies to chiatric diseases such as autism may re- affective disorders [Soares and Mann, 1997]. Close parallels exist amongst the HHV-6 and measles are positively asso- quire the presence of specific genes, an core and associated features of these psy- ciated with peripheral autoantibodies to environmental trigger, and exposure at a chiatric disorders and the wide range of CNS antigens in children with autism particular time during brain develop- physiologic and neurobehavioral distur- [Singh et al., 1998]; studies have not yet ment; all factors, genetic and environ- bances described in neonatally infected been reported regarding such associations mental, must be reconstructed within a animals; in particular, the overlap of signs with autoantibodies in cerebrospinal neurodevelopmental context. Thus, de- of autism spectrum disorders with ele- fluid. velopmental differences in host inflam- ments of the neonatal syndrome is espe- Alterations in T cell subsets may matory and neuroendocrine capacities cially striking. also fit with the hypothesis that increased and in rates of maturation of nervous and Abnormal growth and physiologic susceptibility to specific types of viral in- immune system elements [Rubin et al., profiles have been noted, although the fections may be mediated by regulation 1999a] are likely to contribute to the mechanisms contributing to these distur- of virus-specific receptors and of Th1 vs. differential susceptibility of neuronal and bances are not known. Neonatally in- Th2 immunity, and may provide a link glial populations to pre- or postnatal infected animals are stunted in growth to development of CNS-directed auto- flammatory stressors (infectious, immune) compared to uninfected littermates as immune responses in autism. In conjunc- and impact the phenotypic expression of early as day 4 postinfection [Bautista et tion with reports of an increase in T cells autism and other neurodevelopmental al., 1994; Carbone et al., 1991; Hornig et expressing a “late activated” pattern (i.e., disorders [Briese et al., 1999; Hornig et al., 1999] without demonstrable alter- positive for DR or class II MHC mole- al., 1999]. ations of glucose, growth hormone, in-

202 MRDD RESEARCH REVIEWS ● PATHOGENESIS OF NEURODEVELOPMENTAL DISORDERS ● HORNIG AND LIPKIN sulin-like growth factor-1 [Bautista et al., coding for IL-1␤ have been noted by bright light). Other indices of disturbed 1994], or amount of food ingested [Bau- several investigators following neonatal emotional reactivity in infected rats, in- tista et al., 1995]. They also display al- infection of Lewis rats [Hornig et al., cluding increased defecation in the tered sleep-wake cycles and heightened 1999; Plata-Salamań et al., 1999; Sauder brightly lit open field, were consistent taste preferences for salt-containing solu- and de la Torre, 1999], suggesting the with this hypothesis of increased fearful- tions [Bautista et al., 1994]. Given re- possibility that cytokines may contribute ness and drive to avoid aversive stimuli. ported alterations in other neuropeptide to sleep-wake cycle abnormalities in this Indeed, the more traditional measures of systems following neonatal infection of model as well. The potential contribu- anxiety that were measured in this study, Lewis rats [Plata-Salamań et al., 1999], it tion of dysregulation of autocoids and freezing and thigmotaxis, were actually is intriguing to speculate that disturbed temperature regulation to the pathogen- decreased in infected animals compared salt preferences might result from dys- esis of the neonatal syndrome remains to to controls [Pletnikov et al., 1999b]; regulation of the neuropeptide arginine be studied. Of note, many children with however, these measures are less reliable vasopressin, either through direct infec- autism demonstrate abnormal taste pref- as measures of anxiety at extremely high tion of magnocellular neurons of hypo- erences and sleep disturbances [Wing, levels, where fearfulness and flight re- thalamus or indirect effects on the mag- 1997]. sponses are induced [Davis and Shi, 1999; nocellular division through perturbations Persistent disturbances are also re- King, 1999]. of mineralocorticoid responses (including ported in the cognition, socioemotional Additionally, during acoustic star- potential effects of BDV on mineralocor- behavior and communication, and motor tle testing of neonatally infected animals, ticoid release by the adrenal glands, or on development of neonatally BDV-in- Pletnikov and colleagues found a disso- mineralocorticoid receptors in hypothal- fected animals. Cognitive deficits and ciation between the amplitude of the amus). Alternatively, BDV could influ- unusual emotional reactivity were first startle response and autonomic reactivity: ence salt taste preferences through effects described in Wistar rats, in which spatial whereas infected animals had a signifi- on gustatory neurocircuitry, either at the and aversive learning impairments were cantly lower startle response amplitude level of primary gustatory transduction, found along with increased motor activ- compared to sham-inoculated rats, and sensory transmission via the chorda tym- ity and decreased anxiety responses in both habituation and footshock sensitiza- pani branch of cranial nerve VII, or pro- open field testing under bright light con- tion of their startle responses demon- cessing of taste signals in the rostral por- ditions from 15 weeks postinfection [Dit- strated a normal pattern, autonomic re- tions of the nucleus of the solitary tract, trich et al., 1989]. Similar deficits in spa- sponses (defecation) were higher where primary gustatory nerves termi- tial learning and memory were more [Pletnikov et al., 1999b]. These findings nate for salt sensation [King et al., 1999]. recently confirmed in neonatally infected point to a possible disturbance in integra- A role for a higher order sensory process- Lewis rats 43 to 72 days postinfection, in tion of signals from neural circuits in- ing defect may be a more likely explana- association with the peak of dentate gyrus volved in higher order sensory processing tion than salt depletion or aberrant taste granule cell loss [Rubin et al., 1999b]. (glutamatergic afferents to or efferents discrimination capacity given that neona- Emotional responses of adult Lewis rats from a critical site in primary startle re- tally infected animals do not differ in the infected as neonates appear to depend sponse neurocircuitry, the caudal pontine amount of salt solution consumed in sin- both on testing conditions and age at reticular nucleus), anxiety/fear responses, gle bottle taste acceptance experiments testing. Dittrich et al. [1989] found loco- and autonomic system outputs. Although [Bautista et al., 1994]; nonetheless, the motor hyperactivity and absence of freez- the role of amygdala in fear-potentiation alternative hypotheses have yet to be ex- ing behavior in brightly lit open field of the classic motor aspects of startle re- amined by neurohormonal and serum os- testing of 4 month old Wistar rats in- sponses of infected animals appears to be molality assessments and detailed neuro- fected with BDV as neonates, a finding intact, exaggeration of responses of the pathologic analysis of neural systems which was interpreted as indicative of central nucleus of the amygdala to nor- regulating salt intake, including the nu- abnormally low anxiety responses. How- adrenergic, autonomic signals from locus cleus of the solitary tract. ever, based on a comparison of the aver- coeruleus may be faulty [Koch, 1999], Whether disturbances of circadian siveness of bright and dim illumination possibly accounting for the opposite ef- rhythms relate to direct or indirect effects conditions in 3 to 4 month old, neona- fects of neonatal infection on the motor of BDV infection is similarly unclear; tally infected and sham-inoculated ani- and autonomic components of the startle however, a wide variety of inflammatory mals, Pletnikov et al. [1996b] noted that response. The relationship of these ab- stressors are known to induce sleep-wake hyperactivity of infected animals was normalities of anxiety and fear responses disturbances through shifts in cytokines, greater in bright light conditions than in to developmental maturity and unfolding prostaglandins, and body temperature dim light, whereas the opposite pattern of CNS damage following neonatal in- [Dunn, 1993; Dunn and Swiergiel, 1998; pertained in the control animals. Al- fection was not reported. In this context, Wong et al., 1997]. In studies of the though freezing and thigmotaxic (“wall- we have reported a transient, abnormal retroviruses HIV [Opp et al., 1996] and seeking” behavior consistent with an response to novelty (inhibition of loco- feline immunodeficiency virus [Pros- attempt to escape from the testing ap- motor activity responses upon introduc- pero-Garcia et al., 1994] in rats, sleep paratus) behaviors were more evident in tion to novel environment) at 4 weeks architecture changes are associated with neonatally infected animals in bright light postinfection, when brain levels of the envelope glycoprotein (gp); in the as opposed to dim light open field testing, mRNAs for cytokines associated with case of HIV, intracerebroventricular ad- the mean time spent in freezing behavior decreased exploratory responses, such as ministration of gp 120 also increases during the testing period was consistently IL-1, [Dantzer et al., 1998], were at their mRNA expression for the cytokines, in- lower in infected than in control animals. peak [Hornig et al., 1999]; this observa- terleukin (IL)-1␤ and IL-10 in hypothal- The authors concluded that the increased tion is also consistent with abnormal amus, a brain region crucial for sleep motor activity in bright light represented amygdaloid responses. regulation [Opp et al., 1996]. Intrigu- hyperreactivity of neonatally infected an- Disturbances of complex socio- ingly, increased brain levels of mRNA imals to aversive stimulation (i.e., the emotional behaviors and communication

MRDD RESEARCH REVIEWS ● PATHOGENESIS OF NEURODEVELOPMENTAL DISORDERS ● HORNIG AND LIPKIN 203 known to be altered in conditions such as natally infected rats show asymmetric est functional abnormalities stand in con- autism have also been reported. Play be- protoambulatory (“pivoting”) responses, trast to the reportedly dramatic losses in havior is decreased with respect to both with an increased frequency of falls into a Purkinje cells by 6 weeks postinfection infected animals’ initiation of nondomi- supine position between days 4 and 9 [Eisenman et al., 1999; Hornig et al., nance-related play interactions and re- postinfection—an unusual movement 1999; Weissenbo¨ck et al., 2000] and im- sponse to initiation of play by nonin- never observed in control animals. In ad- ply the possibility of alternate, compen- fected, age- and gender-matched control dition, they exhibit significant delay in satory circuits for maintainence of gait animals or by infected littermates [Plet- righting themselves on a flat surface, and and balance. nikov et al., 1999a]. Given the selective explore the open-field chamber less As seen in adult rats infected with effects of BDV on D2 receptors in the widely through the 9th postnatal day BDV, locomotor activity is increased in adult infection model [Solbrig et al., [Hornig et al., 1999]. Such sensorimotor neonatally infected rats beginning as early 1994; 1996a,b], it is interesting to note processing disturbances suggest early as 4 weeks of age. Interestingly, the de- that this receptor subtype is thought to be functional damage to motor circuitry, in- gree of baseline motor activity in neona- the site of dopamine’s effects on social cluding cerebellum and striatum, and to tally infected rats far exceeds the baseline play behavior [Vanderschuren et al., acetylcholine systems; in addition to levels seen in the adult system. As noted 1997]. Other neuromodulators thought known infection of cerebellum and stri- above, exploratory behavior patterns and to be disrupted in adult BDV infection of atum in the neonatal system, adult infec- adaptation to novel environment are ab- Lewis rats, including monoamines, ace- tions have been associated with losses of normal at 4 weeks after neonatal infec- tylcholine, and opioids [Solbrig et al., choline acetyltransferase-positive fibers tion, as evidenced by prolonged locomo- 1995], also play a role in regulating social before the onset of encephalitis. Thus, it tor inhibition upon introduction to a play [Vanderschuren et al., 1997]. Studies is conceivable that similar damage may novel environment, and suggest dysfunc- of regional monoamine shifts following occur to cholinergic neurons in the neo- tion of the amygdaloid nuclei. This resis- neonatal infections are underway to de- natal system, where immune cell infiltra- tance to novel stimuli is not seen at any termine whether neurochemical aberra- tion also occurs later and is only fleeting. other timepoint through to 12 weeks; tions similar to those in adult-infected Given a recent report by Teitelbaum and indeed, this behavioral inhibition at 4 animals may contribute to these social colleagues indicating early, often tran- weeks is all the more striking given that it play abnormalities. Nucleus accumbens sient, locomotor abnormalities in chil- is only apparent in the first 30 minutes of and striatum, two brain areas affected in dren with autism, including abnormali- testing, following which infected animals both the adult and neonatal rat models, ties of the righting response, crawling, progress to marked hyperactivity for the also impact initiation of play behaviors. and ambulation, [Teitelbaum et al., remainder of the 90 minute test session. Furthermore, these sites receive signals 1998], further examination of the patho- Additionally, infected animals fail to from the amygdaloid nuclei, areas in- genesis of neurodevelopmental distur- show the normal patterns of attenuation volved in the selection of socially appro- bances in this infection-based animal in exploratory activity at 60 and 90 min- priate responses [Vanderschuren et al., model is warranted. utes, consistent with spatial memory def- 1997] and also observed to be heavily Because the cerebellum undergoes icits and hippocampal dysfunction. Sub- infected after adult and neonatal BDV substantial postnatal development in tle increases are noted in mild stereotypic infection. In another intriguing parallel many mammals, it is particularly vulner- behaviors, such as sniffing and rearing, with a core feature of autistic disorder, able to injury from perinatal infection actions which can also serve to assist that of impaired social communication, with any of several viruses including exploration of the environment [Ike- infant-maternal communication appears Borna disease virus, mumps virus, and moto and Panksepp, 1994; Poltyrev and altered following neonatal infections lymphocytic choriomeningitis virus Weinstock, 1997], but not in more se- [Hornig et al., 1999]. Ultrasonic vocal- [Monjan et al., 1971, 1973; Oster-Gran- vere, self-mutilatory repetitive behaviors ization distress calls induced by maternal ite and Herdon, 1985; Rubin et al., [Hornig et al., 1999]. separation are one of the earliest and most 1998]. The observation that many agents Our understanding of the mecha- universal social communication responses may induce similar patterns of damage nisms mediating functional damage to to develop in mammals [Hofer, 1996; suggests that a nonspecific mechanism the Lewis rat host following neonatal Winslow and Insel, 1990], and are nor- may be implicated, such as induction of BDV infection is beginning to expand. mally reduced by social signals (e.g., pres- soluble factors triggered by viral replica- Consistent with previous reports ence of an anesthetized mother or litter- tion. [Narayan et al., 1983; Carbone et al., mate in the testing chamber) and by There is substantial evidence for 1991], we found morphologic alterations serotonergic agents, but increased fol- the role of the cerebellum in motor bein brains of rats infected as newborns, lowing administration of noradrenergic havior and motor learning (for reviews including loss of dentate gyrus granule reuptake inhibitors [Hofer, 1996]. In see [Llinas and Welsh, 1993; Roland, cells and disorganization of cerebellar neonatally infected Lewis rats, ultrasonic 1993; Thompson and Kim, 1996]). In granule cell layer. Cerebellar abnormali- vocalizations are remarkable for increased neonatal BDV infection, overt cerebellar ties included decreased overall size and call frequency and abnormal waveforms dysfunction appears late and is mild to foliation of cerebellum, and thinning of (Hornig and Lipkin, unpublished data). moderate in severity [Hatalski, 1996; cerebellar granule cell layers. Hippocam- The efficacy of these calls in eliciting Hornig et al., 1999]. Only 5% of neona- pal changes in neonatally and adult in- appropriate maternal responses and their tally infected Lewis rats had mild gait fected animals included distinct loss of responsivity to social cues are currently ataxia between 12 and 24 weeks postin- granule cells in dentate gyrus. Previous being explored. fection, but all were impaired in skills investigators reported an absence of cel- Even before neuronal subsets are requiring more complex coordination lular inflammatory response to BDV fol- observed to be depleted in cerebellum, and balance, such as that required to lowing neonatal infection [Narayan et al., the developmental progression of motor maintain balance while walking across a 1983; Herzog et al., 1985; Stitz et al., skills and activity levels is distorted. Neo- dowel [Hornig et al., 1999]. These mod- 1989; Carbone et al., 1991; Sierra-

204 MRDD RESEARCH REVIEWS ● PATHOGENESIS OF NEURODEVELOPMENTAL DISORDERS ● HORNIG AND LIPKIN Honigmann et al., 1993; Bautista et al., neonatally infected and sham-inoculated brain to be even more striking than as- 1994; 1995; Gosztonyi and Ludwig, animals, suggest they cannot be impli- trocytosis. Interestingly, microglia re- 1995; Plata-Salamań et al., 1999; Rott cated. Staining for PECAM on endothe- main activated even at 76 week postin- and Becht, 1995; Rubin et al., 1999a], a lial cells does not differ between infected fection, despite the absence of any phenomenon ascribed to the immaturity and uninfected groups, and although lev- evidence of infection; in contrast, a small of the rat immune system in the postnatal els of ICAM-1 increase on endothelial proportion of astrocytes do become in- period. Humoral immune responses to and other vascular and perivascular cells fected, although astrocytic activation BDV in neonatally-infected animals are of neonatal BD rats at about 4 weeks subsides between 4 and 24 week postin- also reported to be restricted, with anti- postinfection, the most prominent stain- fection. Cerebellar size has been reported BDV antibody titers remaining below ing appears in hippocampus and cerebel- to be reduced, with evidence of reactive 1:10 through 133 days postinfection. lum in addition to cerebral cortex. Thus, astrocytosis as demonstrated by glial [Carbone et al., 1991]. In contrast to the the regional distribution of ICAM-1 does fibrillary acidic protein (GFAP) reactivity many published reports of persistent in- not explain the apparent exclusion of in- as early as 3 days postinoculation, preced- fection without an inflammatory re- flammatory infiltrates from hippocampus ing the identification of BDV proteins in sponse, close serial analysis has revealed and cerebellum at 4 weeks postinfection. the cerebellum. Furthermore, reactivity transient, regionally restricted inflamma- Developmental maturity of the im- of cerebellar astrocytes and loss of cere- tion [Hornig et al., 1999; Sauder and de mune and nervous systems at the time of bellar granule cells occur without signs of la Torre, 1999]. These inflammatory in- exposure to the viral agent are critical to BDV infection in those cell populations filtrates emerge about 4 weeks postinfec- determining inflammatory responses and at all timepoints through to 30 days tion in perivascular areas of motor and ultimate neurodevelopmental outcomes postinfection. Curiously, Purkinje cells parietal cortex, with less marked infil- [Hornig et al., 1999; Rubin et al., appear to be the predominant cerebellar trates in nonhippocampal portions of 1999a]. Animals infected within the first cell population demonstrating BDV an- temporal cortex, thalamus, and basal gan- 12 hours of life demonstrate tolerance tigens, although these cells were previ- glia, and disappear completely by 6 and do not have a robust immune re- ously reported to be retained through day weeks postinfection. Despite nearly com- sponse to the virus [Hornig et al., 1999]. 30 postinfection [Bautista et al., 1995]. plete loss of the dentate gyrus, marked In contrast, animals infected with low However, our investigations indicate that loss of cerebellar Purkinje cells, and thin- titer stocks or administered virus after the by day 42 postinfection, Purkinje cell ning of granular cell layers in cerebellum first 12 hours of life may have marked populations are selectively depleted. Sim- by this timepoint, no such infiltrates are inflammatory cell infiltrates and en- ilarly, at 7 months after neonatal infec- present in these areas at 2, 4, or 6 weeks hanced morbidity and mortality. tion, Eisenman and colleagues report postinfection. Areas of inflammation are The manner in which infection re- 75% depletion of Purkinje cells [Eisen- also distinct from those areas showing the sults in loss of select neuronal subsets in man et al., 1999]. greatest amount of apoptosis (periven- this model system is not yet known. Astrocytosis and microgliosis occur tricular germinal layer, dentate gyrus, Mechanisms may be both direct and in- in all brain regions by 3 weeks postinfec- granular layer of cerebellum). Immuno- direct. Clearly, infection alone is an in- tion. The onset and distribution of glial histochemical analysis of infiltrates indi- sufficient signal, as many neuronal pop- cell proliferation coincides with neuronal cates that they are comprised primarily of ulations remain persistently infected in loss yet is sustained through 24 weeks T cells with approximately equal num- neonatal BD without evident reduction postinfection, after neuronal cell death bers of CD4ϩ and CD8ϩ cells [Weis- of cell numbers. Cells that are lost due to wanes. Astrocyte and microglia mor- senbo¨ck et al., 2000]. neonatal infection, predominantly found phology is consistent with activation (in- Curiously, brain lymphocytes from in cerebral cortex, dentate gyrus, and the creased cytoplasm; short, thickened pro- 4 week old, neonatally infected rats do Purkinje cell layer of cerebellum, appear cesses; additionally, in microglia, more not demonstrate cytotoxic activity to be lost exclusively through apoptosis intense staining with OX42). In hip- against BDV antigens [Hornig, Briese, [Hornig et al., 1999; Weissenbo¨ck et al., pocampus, gliosis is most evident in den- Planz, and Lipkin, unpublished data], 2000]. tate gyrus. In cerebellum, gliosis is suggesting that these T cells are not spe- Apoptotic cells, characterized by equally prominent in white and grey cific. Furthermore, neonatally thymecto- shrinkage, hypereosinophilic cytoplasm, matter. Curiously, microglia express mized, infected animals do not differ nuclear pyknosis and karyorrhexis, and MHC Class I and II, CD4 and CD8 from sham thymectomized, infected an- signal on transferase dUTP-biotin nick (OX8 and CD8b) molecules on their imals in degree of dentate gyrus damage, end labeling (TUNEL) assay, peaked at surface [Weissenbo¨ck et al. 2000]. Purkinje cell loss, or cortical atrophy, four weeks p.i., with most marked pa- Astrocytes and microglia are acti- despite successful ablation of inflamma- thology in dentate gyrus and cortical lay- vated in the absence of infection, be it tion at the 4 week timepoint by the neo- ers 5 and 6 of retrosplenial and cingulate directly by BDV or indirectly through natal thymectomy procedure [Hornig, cortex. Although apoptosis is described elaboration of soluble factors by other Stitz, and Lipkin, unpublished data]. in hippocampus of developing animals as cell types. Given the role of astrocytes in How these presumably activated, but late as day 7 to 10 of postnatal life, it is guiding migration of granule cells during nonspecific T cells are attracted to, and not found at later timepoints [Toth et al., cerebellar development, an assessment of transiently retained in selected regions of 1998]. It is intriguing to speculate that the frequency of astrocyte reactivity CNS and not in others is an intriguing, BDV may influence the expression of without viral infection in conjunction but unanswered question. Likely candi- age-related programs associated with with studies of apoptosis in limbic struc- dates for direct viral effects include cell normal, development-associated apopto- tures would aid our understanding of the adhesion molecules and chemokines. sis through the direct or indirect elabo- relative contributions of migrational fail- Levels and distribution of the cell adhe- ration of soluble factors. ure and programmed cell death in the sion molecules PECAM and ICAM-1, as We observe reactivity and prolifer- evolution of BD neuropathogenesis. measured by immunohistochemistry in ation of microglial cells throughout the Even more intriguing may be the mech-

MRDD RESEARCH REVIEWS ● PATHOGENESIS OF NEURODEVELOPMENTAL DISORDERS ● HORNIG AND LIPKIN 205 anism by which microglia are activated in necrosis factor family, interferons), the Recent studies concerning cyto- the absence of infection. In neonatal TGF-␤ superfamily factors (including kine expression during neonatal infection HIV-1 infection, for instance, diffuse mi- TGF-␤1, 2, 3; GDNF), and the classic provide a converging view of the poten- croglial activation and reactive astroglio- neurotrophic factors (NGF, BDNF, NT3, tial importance of cytokines as mediators sis occur along with impaired brain NT4/5). A large subset of the neu- of BDV-related CNS injury in neonatal- growth and developmental delays [Ep- ronotrophic, hematolymphoietic cyto- ly-infected rats [Hornig et al., 1999; stein and Gelbard, 1999]. However, in kines may be roughly categorized ac- Plata-Salamań et al., 1999; Sauder and de contrast to neonatal BD, microglia inter- cording to their origin from one of two la Torre, 1999]. Cytokine expression nalize virus in neonatal HIV-1 infection types of T-helper cells: Th1 (cell-medi- changes over time in different brain re- and replication can occur upon chronic ated immunity and stimulation of anti- gions, with maximal alteration occurring exposure to proinflammatory cytokines gen-presenting cells) or Th2 (humoral or at 4 weeks. Higher levels of mRNAs for [Janabi et al., 1998]. Two other findings B-cell mediated immunity). The poten- cytokine products of CNS macrophages/ regarding microglia-related injury in tial mechanisms of cytokine-mediated microglia (IL-1␣, IL-1␤, IL-6, TNF-␣) HIV-1 infection may be relevant to an damage in the context of the developing are noted in hippocampus, amygdala, understanding of mechanisms in BD brain include: direct effects on neuronal cerebellum, prefrontal cortex, and nu- pathogenesis: 1) production of the neu- elements; activation or suppression of cleus accumbens [Hornig et al., 1999]. rotoxin, quinolinic acid, is substantially second messenger/intracellular signaling Elevated levels of these proinflammatory greater in uninfected than in HIV-1 in- pathways; induction of shifts in excito- cytokines were first apparent at 2 weeks, fected monocytes following lipopolysac- toxic elements such as quinolinic acid or peaked at 4 weeks, and then declined at 6 charide or interferon-␥ stimulation [Not- acute phase proteins such as neopterin or and 12 weeks. No alterations in other tet et al., 1996]; and 2) the viral protein, ␤-2-microglobulin; direct alterations of proinflammatory cytokines, including gp41, may act indirectly to induce neu- neuronal function (e.g., inhibition of IL-2, IL-3, TNF-␤, and IFN-␥, were rotoxicity by triggering IL1 ␤ production long-term potentiation in hippocampus); observed. Given that production of sev- in microglia, thereby stimulating iNOS activation or suppression of glial cells; or eral of these proinflammatory cytokines production and NO generation by astro- alteration of glial cell proliferation or dif- is unique to T cells, B cells, mast cells, cytes [Hu et al., 1999]. General mecha- ferentiation (including expression of ad- and bone marrow stromal cells, and not nisms of CNS injury following microglial hesion molecules such as the integrins) to macrophages or microglia, these data activation also appear to relate to differ- [Benveniste, 1997; Mehler et al., 1996]. suggest that BDV may exert a selective ential regulation of MHC and other mol- Given that the postnatal expression of effect on cells of microglial or macro- ecules on microglia [Stoll and Jander, neuronotrophic cytokine and cytokine phage lineage. 1999]. Whether the unusual pattern of receptor mRNAs in brain differs for each Following neonatal infection, upregulation of MHC, CD4, and CD8 cytokine [Benveniste, 1997], and that the BDV influences the expression of apop- molecules observed on uninfected, acti- sensitivity of neuronal populations to the tosis-related products. Increased levels of vated microglia in neonatal BDV infec- trophic or apoptosis-inducing effects of mRNAs coding for FAS and ICE tion might explain the pattern of damage cytokines changes during development, (caspase-1), two promotors of apoptosis, observed is not known. wide variation in the patterns of virus- and decreased mRNA for bcl-x, a factor Higher levels of message for tissue induced, cytokine-related damage would that inhibits apoptosis, were identified in factor (TF) have been found in infected be expected, depending on the relative hippocampus, amygdala, prefrontal cor- hippocampus [Gonzalez-Dunia et al., maturity of the evolving nervous system tex, nucleus accumbens, and cerebellum 1996]. TF is a member of the class II at the time of infection. In addition, cell [Hornig et al., 1999]. These findings are cytokine receptor family primarily pro- loss induced by either BDV or develop- consistent with promotion of apoptosis duced by astrocytes that plays important mentally-programmed changes may alter throughout the brains of rats neonatally roles in cellular signal transduction, brain the capacity of resident CNS cells to both infected with BDV by at least two strat- function, and neural development produce and respond to neuronotrophic egies. A host of excitants or neurotoxins through its effects on coagulation pro- cytokines. including arachidonic acid, platelet-acti- Ϫ tease cascades. Although this may be one One of the primary mechanisms of vating factor, free radicals (NO, O2 ), mechanism by which BDV may alter host defense following viral infection be- glutamate, quinolinate, cysteine, cyto- CNS development [Gonzalez-Dunia et gins with the induction of interferon-␥ kines (TNF-␣, IL1-␤, IL-6), amines, and al., 1996], cerebellar changes cannot be (IFN-␥) and other cytokines, which in as yet unidentified factors arising from explained by this mechanism as TF up- turn initiate a cascade of host responses in stimulated macrophages and possibly re- regulation is not observed in cerebellum a wide variety of cell types. In the CNS, active astrocytes may also influence apo- despite prominent astrocytosis. Further- IFN-␥ modulates oligodendrocyte, neu- ptosis by excessive activation of N- more, BDV infection of astrocytes ap- ronal and glial cell functions, and is im- methyl-D-aspartate (NMDA) receptors pears to be required for TF upregulation portant in activating glial cells to produce [Lipton, 1996]. Interestingly, Gosztonyi [Gonzalez-Dunia et al., 1996], and cere- mediators of cell damage or death, in- and Ludwig [1995] have proposed that bellar astrocytes are rarely infected cluding toxic intermediates of nitrogen the targeted pathology of BDV for two [Hornig et al., 1999]. and oxygen, and complement compo- hippocampal cell layers, stratum oriens One means by which a virus might nents [St. Pierre et al., 1996]. Viral dam- and stratum radiatum, may be due to disrupt neural function and development age to neurodevelopmental circuitry may their rich concentration of glutamate and in the absence of inflammation is through thus parallel the production of these aspartate receptors, and preliminary re- the induction of neuronotrophic cyto- downstream mediators following IFN-␥ sults from our laboratory indicate re- kines. Neuronotrophic cytokines comprise induction, and provide a means by which gional upregulation at 4 weeks postinfec- a burgeoning set of immunoregulatory BDV might disrupt brain cell differenti- tion of a non-NMDA glutamate molecules, including the hematolym- ation and function without inflammatory receptor, the calcium-permeable AMPA phoietic factors (e.g., interleukins, tumor cell infiltration. receptor, GluR1 (Hornig and Lipkin,

206 MRDD RESEARCH REVIEWS ● PATHOGENESIS OF NEURODEVELOPMENTAL DISORDERS ● HORNIG AND LIPKIN unpublished data). Consistent with re- cific neural cells and circuits. Future Bolton P, Pickles A, Harrington, R, et al. 1992. gion-specific findings of apoptosis by work should focus on dissecting the Season of birth: issues, approaches and findings for autism. J Child Psychol Psychiatry TUNEL analysis, this upregulation is mechanisms of developmental neuropa- 33:509–530. most evident on granule cells in dentate thology in animal models and using clues Brai M, Accardo P, Bellavia D. 1994. Polymor- gyrus and at synapses of cells in molecular derived from these more simple systems to phism of the complement components in hu- cell layer of cerebellum that terminate on target infectious disease investigation. f man pathology. Ann Ital Med Int 9:167–172. Purkinje cells (presumably, Bergmann Briese TB, Hornig M, Lipkin WI. 1999. 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