. Author manuscript; available in PMC: 2014 Jul 1.

Published in final edited form as: Neurosci Biobehav Rev. 2013 Jan 10;37(6):1120–1138. doi: 10.1016/j.neubiorev.2013.01.007

Table 3.

Animal models of Tourette syndrome based on immunization with microbial immunogen or mimics.

Exposure	Controls/ comparator s	Route of exposure	Species	Strain	Agent of BBB breach	Pathologic findings	Behavior abnormalities	Citation
GAS (M6 type) homogenate	Vehicle (PBS)	sc	Mouse	SJL/J	CFA, 1° immunizati on IFA, 2° boosts (3- week intervals)	↑ anti-brain antibodies in serum Brain-reactive GAS- immunized mouse sera were immuno-reactive against strep antigens ↑ IgG deposits in STR, CBLM, lateral HYP, nuclei in thalamus, pons, and brainstem Presence of serum anti-brain antibodies and IgG deposits immunoreactive against CBLM (deep cerebellar nuclei) correlated with degree of stereotypic behaviors (rearing)	↑ rearing ↓ coordination ↓ exploration, social investigation ↑ submissive behaviors ↑ defense-escape behaviors ↑ grooming ↓ olfactory discrimination learning ↓ errors and inter- response time in reversal learning and memory task	Hoffman et al., 2004; Yaddanapudi et al., 2010
Sera from GAS- immunized mice	IgG- depleted GAS sera PBS mouse sera IgG- depleted PBS sera	IV injection into tail vein, ip injection of LPS	Mouse	Male SJL/J	LPS	↑ IgG deposits in Hc and periventricular area IgG depletion prior to injection of GAS-immunized mouse sera decreases binding in brain and abrogates behavioral effects	↑ rearing ↓ exploration, social investigation ↑ submissive behaviors ↑ defense-escape behaviors ↑ grooming	Yaddanapudi et al., 2010
GAS (M18 type) cell wall components	Vehicle (PBS) wall components	sc injection of CFA and IFA, ip injection of B. pertussis	Rat	Male Lewis	CFA + heat- inactivated mycobacter ia + B. pertussis, at 1° immuni zation IFA, 2° boosts (2- week intervals)	↑ IgG deposits in STR, thalamus and frontal Cx ↑ DA levels in frontal Cx, entopeduncular nucleus (human globus pallidus equivalent) ↓ glutamate levels in frontal Cx Sera from strep-immunized mice were immunoreactive with strep antigens, tubulin and DA receptors DRD1 and DRD2 GAS rat sera induced CAM kinase II activity; activated was reduced after IgG depletion of sera	↓ food manipulation capacity ↓ narrow beam walking (unimpaired wide beam) ↑ induced grooming ↓ motor abnormalities with DRD2 blocker (haloperidol) ↓ induced grooming with selective serotonin reuptake inhibitor, paroxetine	Brimberg et al., 2012
Poly I:C (double- stranded RNA viral mimic), mid- gestation	Vehicle (PBS)	ip	Mouse	C57BL/6J C57BL/6N	None	↓ T regulatory cells ↑ IL-6 and IL-17 production by CD4⁺ T cells Bone marrow transplantation reconstitutes immune system and reverses stereotypic, social and communication deficits	↑ self-grooming ↑ marble burying ↑ ultrasonic communication deficits ↓ sociability ↓ PPI	Malkova et al., 2012; Hsaio et al., 2012
Poly I:C (double- stranded RNA viral mimic), late gestation	Vehicle (PBS)	ip	Mouse	C57BL/6J	None	↓ neurogenesis (reduced generation of intermediate progenitor cells, ↓ Cux1⁺ neurons) ↑ neuronal apoptosis Barin abnormalities reversed by single dose of non- steroidal anti-inflammatory COX-2 inhibitor, carprofen	↓ early motor coordination ↓ PPI ↑ locomotor activity in novel environment ↓ habituation to novelty Behavioral deficits reversed by single dose of non-steroidal anti- inflammatory COX-2 inhibitor, carprofen	DeMiranda et al., 2010
LPS, mid- gestation	Vehicle (PBS)		Rat	Wistar	None	↓ DA synthesis in STR No glial activation evident	↑ repetitive behaviors in male offspring	Kirsten et al., 2012

Key: BBB, blood-brain barrier; CaM kinase II, calcium/calmodulin-dependent protein kinase II; CBLM, cerebellum; CFA, complete Freund’s adjuvant; Cx, cortex; DA, dopamine; GAS, Group A Streptococcus; Hc, hippocampus; HYP, hypothalamus; IFA, incomplete Freund’s adjuvant; IL, interleukin; ip, intraperitoneal; IV, intravenous; LPS, lipopolysaccharide; poly I:C, polyinosinic:polycytidylic acid; PBS, phosphate-buffered saline; PPI, prepulse inhibition; s, soluble; sc, subcutaneous; STR, striatum; TS, Tourette syndrome