Psychiatry Research 215 (2014) 494–496
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Clonidine in Tourette syndrome and sensorimotor gating
To the Editors: Tourette syndrome (TS) is characterized by motor and vocal tics, with a pre-pubertal age of onset, a waxing and waning course, and improvement in symptoms in adulthood (Eapen and Crncec, 2009). Problems with the sensorimotor gating system as evidenced by reduced Prepulse Inhibition (PPI) compared to normal control subjects have been described in TS (Castellanos et al., 1996) leading to suggestions that deficits in sensorimotor gating are associated with the generation of tics. Leckman et al. (1993) reported that 93% of TS patients experienced premonitory urges while 84% reported that tics were associated with a feeling of relief implicating brain regions involved in the processing of sensorimotor information in the pathobiology of tic disorders (Leckman et al., 1993). In this regard, a brain network of paralimbic areas such as the anterior cingulate and the insular cortex (ACC), the supplementary motor area (SMA) and the parietal operculum has been shown to be activated before the tic onset, corresponding with the premonitory sensation, while sensorimotor areas including the cerebellum and superior parietal lobule are activated at the onset of tic action (Bohlhalter et al., 2006). Further, electrical stimulation of the SMA has been shown to result in an experience similar to premonitory sensation (Fried et al., 1991), and there is limited data indicating that transcranial magnetic stimulation (TMS) involving the SMA may reduce tic symptoms (Mantovani et al., 2007, 2006). This is also consistent with the finding that the SMA, which is implicated in the premonitory sensations in tics (Hampson et al., 2009), is the major mesocortical target of dopaminergic projections from the substantia nigra and ventral tegmentum (Le Moal and Simon, 1991). When the premonitory urges, referred to as the “relentless drumbeat” (Leckman et al., 2006), are responded to by the motor tic, this relieves the premonitory sensation and a reinforcing “urge-tic-relief” cycle is established which is further maintained by procedural learning and habit formation. It is of interest that tic symptoms in many patients get better by adulthood, and this is speculated to be due to brain maturation and the opportunities for the frontal cortices to be more efficiently connected to the striatum. While remitted patients show a similar lack of the acoustic startle reflex PPI, indicating the same sensorimotor gating abnormalities, they show more differential activation of left caudate and posterior cerebellum suggesting that they have made compensatory connections (Leckman et al., 2010a). In this regard it is to be noted that smaller caudate volume has been shown to indicate poor prognosis with continued severity of symptoms in adulthood (Bloch et al., 2005). Further, it has been 0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.10.009
found that in TS, there is a smaller number of parvalbuminexpressing fast-spiking GABA-ergic and cholinergic interneurons in the dorsal striatum while there is a greater number and density of these in the globus pallidus. This has led to the suggestion that abnormal neuronal migration is the reason for this, as a normal number of neurons is generated but there is abnormal distribution between striatum and globus pallidus (Kataoka et al., 2010). This in turn may be due to the fact that in TS, there are substantially fewer fast spiking GABA-ergic interneurons in the striatum that orchestrate neural oscillation; for effective sensory gating, one needs the capacity to sustain neural oscillations in the basal ganglia (Leckman et al., 2010b). Thus, it seems that relatively smaller number of these cells in the dorsal lateral striatum might be a key factor in the generation of tics. Several studies have shown that Clonidine, an α (2)-adrenoceptor agonist, is effective in relieving tics, and the mechanism of action is thought to be linked to clonidine's effect on inhibitory learning resulting from reduced noradrenergic activity (Katini et al., 2011). Further, a recent study in schizophrenia suggested that clonidine may exert beneficial effects through improving prefrontal cognitive function and inhibitory control (Oranje and Glenthoj, 2013). This paper reported on a double blind, placebo-controlled, randomized, cross-over study involving schizophrenia patients and normal healthy controls. They found that clonidine significantly increased percentage PPI in the patients compared with placebo, to such levels that it no longer differed significantly from the healthy controls. However, none of the dosages of Clonidine increased sensitization or influenced habituation. Thus, clonidine restored PPI in these patients which suggests that the clinical effectiveness of clonidine in ameliorating tics may be the result of specific effects on the sensorimotor gating mechanisms. In addition to the clinical relevance and the neurophysiological significance of the effect of Clonidine in TS, there may also be an opportunity to elucidate the genetic underpinnings of the pathophysiological abnormalities and the potential for individualized treatments in TS. In this regard, good clinical response to clonidine was recently reported in a TS patient with a well-defined pathological genotype, namely disruption of the IMMP2L gene (Katuwawela and Cavanna, 2012). Therapeutic response is often a function of the pathological genotype which can have profound implications for understanding both the pathology and response to therapy – which is particularly relevant in this case as IMMP2L is one of the few genes that has been recurrently disrupted in TS (Patel et al., 2011; Petek et al., 2001) and in each case the disruption halts the convergent transcription of IMMP2L across LRRN3, the gene located within intron 3 of IMMP2L on the opposing DNA strand (Clarke et al., 2012). Furthermore, LRRN3, a brain enriched neuronal transmembrane leucine rich repeat protein gene is localized within the genomic region most commonly duplicated in ASD (Maestrini et al., 2010; Pagnamenta et al., 2010) and LRRN3's closest relation LRRN1 is also duplicated in ASD
Letter to the Editor / Psychiatry Research 215 (2014) 494–496
(Davis et al., 2009), indicating that dose increases for these two closely related molecules are pathogenic for ASD and TS. The rub being that LRRN1 has a well established role in brain boundary formation during development and in restricting neuronal cell migration and mixing between brain compartments (Tossell et al., 2011). Moreover, ectopic over-expression of Lrrn1 in the chick results in the mixing of cells between brain compartments (Tossell et al., 2011). LRRN1 function in brain boundary formation appears certain to relate to an as yet unidentified ligand that regulates inter-neuronal affinity (Tossell et al., 2011). Competitive binding as it relates to inter-neuronal ligand based affinity is now a pathogenic theme in TS and ASD (Clarke et al., 2012). This pathogenetic model for TS integrates all five of the genes uniquely disrupted in TS within a single competitive neuropathogenetic chain of events comprising the full complement of known neurexin post-synaptic cell adhesion ligand gene families. Interestingly, LRRTM3, another neuronal leucine rich repeat (LRR) transmembrane closely related to LRRN3 has been linked with ASD and TS through the neurexin connexus (Clarke et al., 2012). LRRTM3 is just one of the full complement of neurexin post-synaptic cell adhesion ligand gene families now implicated in TS (Clarke et al., 2012). Balance within the neurexin trans-synaptic connexus appears essential in regulating neuronal circuitry as it pertains to TS and ASD. In turn, the imbalance in neuronal circuitry associated with an imbalance in the neurexin connexus (Clarke et al., 2012) may provide a by-pass to normal gating mechanisms. It is also of interest that LRRN3 and LRRTM3, two neuronal leucine rich repeat (LRR) transmembrane protein genes found associated with ASD are both found nested within introns of genes that have been repeatedly disrupted in TS namely IMMP2L and CTNNA3, respectively (NCBI Build 37.2, 2011) (Clarke et al., 2012). LRRTM3 and LRRN3 are related by virtue of their extracellular LRR ligand binding domains. An improved understanding of LRRN ligand binding is likely to have a profound impact on understanding the molecular basis of ASD and TS pathology as LRRN3's closest relation LRRN1 is known to regulate boundary formation within the developing brain, restricting neuronal cell migration/ mixing between compartments, presumably as a direct function of intercellular ligand affinity (Tossell et al., 2011). Any relaxation in the specificity of neuronal connections associated with the upregulation of LRRN3 or its ligand(s) or any of the neurexin cell adhesion ligands implicated in the TS model (Clarke et al., 2012) may permit aberrant circuitry formation between compartments which in turn may provide a by-pass to normal gating mechanisms. It may well be that neuronal cell adhesion ligands have multiple overlapping roles in terms of signal transmission/maintenance and regional connectivity resulting in different phenotypic presentations, all of which may have sensorimotor gating abnormalities but mediated through different neurotransmitter circuitry. In this regard, previous studies in animals and humans have shown that experimentally-induced PPI deficits can be removed by the administration of antipsychotic agents and that PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable (Swerdlow et al., 2006). These investigators observed that PPI disrupted by the norepinephrine alpha-1 agonist, cirazoline was prevented by clonidine but not haloperidol while PPI disrupted by the D1/D2 agonist apomorphine was prevented by D2 antagonist haloperidol but not clonidine. Such differential neurochemical pathways may provide valuable clues into the pathogenesis of different clinical manifestations or disorders arising from similar pathogenetic processes involving PPI. Further, sensorimotor gating abnormalities have been reported in a number of developmental and psychiatric disorders although there is debate as to whether the diversity of disorders exhibiting deficient PPI represents diagnostic overlaps or
495
comorbidities (Geyer, 2006). Nevertheless, it is, thus, not inconceivable that the ability of clonidine and other tic-suppressant medication to enhance short interval, “automatic” gating reflects a mechanism that is relevant to their therapeutic properties in TS and other related psychiatric disorders. Further, it appears that the neurophysiological deficits such as PPI abnormalities arising from abnormalities in circuitry formation during development may be mediated through specific gene involvement and clonidine restores this, possibly via restoration of impaired prefrontal cortical functions in those patients where the relevant circuitry is involved. It could be argued that, if neurexin-ligand cell adhesion was instrumental in both signal transmission/maintenance and regional demarcation and connectivity during development, then copy number variation doseeffects of the ligands could affect either or both of the above events to different degrees based on the underlying genetic background resulting in different developmental outcomes. Findings built on previous work suggest that at least some genes expressed peripherally are relevant for central nervous system (CNS) pathology in the brain of individuals with TS (Gunther et al., 2012) but it is to be noted that correlations between microarray analysis of peripheral blood gene expression in Tourette syndrome may have no reflection on CNS pathology and provide no reliable indication as to the pathogenetic phenotype in these patients. We believe the neuropathogenetic model described by Clarke et al. (2012) provides a suitable framework for testing the underlying pathogenetic processes and development of new treatment strategies in TS and related disorders. In this regard, future studies are indicated using mouse models to elucidate the developmental effects of upregulation of LRRN3 and the response to clonidine.
References Bloch, M.H., Leckman, J.F., Zhu, H., Peterson, B.S., 2005. Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology 65, 1253–1258. Bohlhalter, S., Goldfine, A., Matteson, S., Garraux, G., Hanakawa, T., Kansaku, K., Wurzman, R., Hallett, M., 2006. Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain 129, 2029–2037. Castellanos, F.X., Fine, E.J., Kaysen, D., Marsh, W.L., Rapoport, J.L., Hallett, M., 1996. Sensorimotor gating in boys with Tourette's syndrome and ADHD: preliminary results. Biological Psychiatry 1 (39), 33–41. Clarke, R.A., Lee, S., Eapen, V., 2012. Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism. Translational Psychiatry 2, e158. Davis, L.K., Meyer, K.J., Rudd, D.S., Librant, A.L., Epping, E.A., Sheffield, V.C., 2009. Novel copy number variants in children with autism and additional developmental anomalies. Journal of Neurodevelopmental Disorders 1, 292–301. Eapen, V., Crncec, R., 2009. Tourette syndrome in children and adolescents: special considerations. Journal of Psychosomatic Research 67, 525–532. Fried, I., Katz, A., McCarthy, G., Sass, K.J., Williamson, P., Spencer, S.S., Spencer, D.D., 1991. Functional organization of human supplementary motor cortex studied by electrical stimulation. J. Neurosci. 11, 3656–3666. Geyer, M.A., 2006. The family of sensorimotor gating disorders: comorbidities or diagnostic overlaps? Neurotoxicity Research 10, 211–220. Gunther, J., Tian, Y., Stamova, B., Lit, L., Corbett, B., Ander, B., Zhan, X., Jickling, G., Bos-Veneman, N., Liu, D., Hoekstra, P., Sharp, F., 2012. Catecholamine-related gene expression in blood correlates with tic severity in Tourette syndrome. Psychiatry Research 200, 593–601. Hampson, M., Tokoglu, F., King, R.A., Constable, R.T., Leckman, J.F., 2009. Brain areas coactivating with motor cortex during chronic motor tics and intentional movements. Biological Psychiatry 65, 594–599. Katini, E., Cassaday, H.J., Hollis, C., Jackson, G.M., 2011. The normal inhibition of Associations is Impaired by clonidine in Tourette syndrome. Journal of the Canadian Academy of Child and Adolescent Psychiatry 20, 96–106. Kataoka, Y., Kalanithi, P.S., Grantz, H., Schwartz, M.L., Saper, C., Leckman, J.F., Vaccarino, F.M., 2010. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. Journal of Comparative Neurology 518, 277–291. Katuwawela, I., Cavanna, A.E., 2012. Good response to clonidine in tourette syndrome associated with chromosomal translocation involving the IMMP2L gene. Journal of Psychiatry and Clinical Neuroscience 24, E17. Le Moal, M., Simon, H., 1991. Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiological Review 71, 155–234.
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Letter to the Editor / Psychiatry Research 215 (2014) 494–496
Leckman, J.F., Bloch, M.H., Smith, M.E., Larabi, D., Hampson, M., 2010b. Neurobiological substrates of Tourette's disorder. Journal of Child and Adolescent Psychopharmacology 20, 237–247. Leckman, J.F., Vaccarino, F.M., Kalanithi, P.S., Rothenberger, A., 2006. Annotation: Tourette syndrome: a relentless drumbeat–driven by misguided brain oscillations. Journal of Child Psychiatry and Psychology 47, 537–550. Leckman, J.F., Walker, D.E., Cohen, D.J., 1993. Premonitory urges in Tourette's syndrome. American Journal of Psychiatry 150, 98–102. Leckman, J., Zebardast, N., Crowley, M.J., 2010a. Deficits in prepulse inhibition persist in individualswhose Tourette syndrome has remitted. Biological Psychiatry 67, 112S. Mantovani, A., Leckman, J.F., Grantz, H., King, R.A., Sporn, A.L., Lisanby, S.H., 2007. Repetitive transcranial magnetic stimulation of the supplementary motor area in the treatment of Tourette syndrome: report of two cases. Clinical Neurophysiology 118, 2314–2315. Mantovani, A., Lisanby, S.H., Pieraccini, F., Ulivelli, M., Castrogiovanni, P., Rossi, S., 2006. Repetitive transcranial magnetic stimulation (rTMS) in the treatment of obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). International Journal of Neuropsychopharmacology 9, 95–100. Maestrini, E., Pagnamenta, A.T., Lamb, J.A., Bacchelli, E., Sykes, N.H., Sousa, I., 2010. Highdensity SNP association study and copy number variation analysis of the AUTS1. and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Molecular Psychiatry 15, 954–968. Oranje, B., Glenthoj, B.Y., 2013. Clonidine normalizes sensorimotor gating deficits in patients with schizophrenia on stable medication. Schizophrenia Bulletin 39 (3), 684–691, http://dx.doi.org/10.1093/schbul/sbs071. Pagnamenta, A.T., Bacchelli, E., de Jonge, M.V., Mirza, G., Scerri, T.S., Minopoli, F., 2010. Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biological Psychiatry 68, 320–328. Patel, C., Cooper-Charles, L., McMullan, D.J., Walker, J.M., Davison, V., Morton, J., 2011. Translocation breakpoint at 7q31 associated with tics: further evidence for IMMP2L as a candidate gene for Tourette syndrome. European Journal of Human Genetics 19, 634–639. Petek, E., Windpassinger, C., Vincent, J.B., Cheung, J., Boright, A.P., Scherer, S.W., Kroisel, S.W., Wagner, K., 2001. Disruption of a novel gene (IMMP2L) by a
breakpoint in 7q31 associated with Tourette syndrome. American Journal of Human Genetics 68, 848–858. Swerdlow, N.R., Bongiovanni, M.J., Tochen, L., Shoemaker, J.M., 2006. Separable noradrenergic and dopaminergic regulation of prepulse inhibition in rats: implications for predictive validity and Tourette syndrome. Psychopharmacology (Berl) 186, 246–254. Tossell, K., Andreae, L.C., Cudmore, C., Lang, E., Muthukrishnan, U., Lumsden, A., Gilthorpe, J.D., Irving, C., 2011. Lrrn1 is required for formation of the midbrainhindbrain boundary and organiser through regulation of affinity differences between midbrain and hindbrain cells in chick. Developmental Biology 352, 341–352.
Valsamma Eapen n, Philip Ward, Department of Infant, Child and Adolescent Psychiatry, Academic Unit of Child Psychiatry, University of New South Wales, South West Sydney, Sydney, NSW, Australia E-mail address: [email protected] (V. Eapen). Raymond Clarke Department of Human Genetics, Ingham Institute, School of Medicine, University of Western Sydney, Sydney, NSW, Australia Received 11 September 2012 12 September 2013 15 October 2013 Available online 23 October 2013
n Correspondence to: LI, Mental Health Centre, Liverpool Hospital, Elizabeth Street, NSW 2170, Australia. Tel.: þ61 2 96164364.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Letter to the Editor
Clonidine in Tourette syndrome and sensorimotor gating
To the Editors: Tourette syndrome (TS) is characterized by motor and vocal tics, with a pre-pubertal age of onset, a waxing and waning course, and improvement in symptoms in adulthood (Eapen and Crncec, 2009). Problems with the sensorimotor gating system as evidenced by reduced Prepulse Inhibition (PPI) compared to normal control subjects have been described in TS (Castellanos et al., 1996) leading to suggestions that deficits in sensorimotor gating are associated with the generation of tics. Leckman et al. (1993) reported that 93% of TS patients experienced premonitory urges while 84% reported that tics were associated with a feeling of relief implicating brain regions involved in the processing of sensorimotor information in the pathobiology of tic disorders (Leckman et al., 1993). In this regard, a brain network of paralimbic areas such as the anterior cingulate and the insular cortex (ACC), the supplementary motor area (SMA) and the parietal operculum has been shown to be activated before the tic onset, corresponding with the premonitory sensation, while sensorimotor areas including the cerebellum and superior parietal lobule are activated at the onset of tic action (Bohlhalter et al., 2006). Further, electrical stimulation of the SMA has been shown to result in an experience similar to premonitory sensation (Fried et al., 1991), and there is limited data indicating that transcranial magnetic stimulation (TMS) involving the SMA may reduce tic symptoms (Mantovani et al., 2007, 2006). This is also consistent with the finding that the SMA, which is implicated in the premonitory sensations in tics (Hampson et al., 2009), is the major mesocortical target of dopaminergic projections from the substantia nigra and ventral tegmentum (Le Moal and Simon, 1991). When the premonitory urges, referred to as the “relentless drumbeat” (Leckman et al., 2006), are responded to by the motor tic, this relieves the premonitory sensation and a reinforcing “urge-tic-relief” cycle is established which is further maintained by procedural learning and habit formation. It is of interest that tic symptoms in many patients get better by adulthood, and this is speculated to be due to brain maturation and the opportunities for the frontal cortices to be more efficiently connected to the striatum. While remitted patients show a similar lack of the acoustic startle reflex PPI, indicating the same sensorimotor gating abnormalities, they show more differential activation of left caudate and posterior cerebellum suggesting that they have made compensatory connections (Leckman et al., 2010a). In this regard it is to be noted that smaller caudate volume has been shown to indicate poor prognosis with continued severity of symptoms in adulthood (Bloch et al., 2005). Further, it has been 0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.10.009
found that in TS, there is a smaller number of parvalbuminexpressing fast-spiking GABA-ergic and cholinergic interneurons in the dorsal striatum while there is a greater number and density of these in the globus pallidus. This has led to the suggestion that abnormal neuronal migration is the reason for this, as a normal number of neurons is generated but there is abnormal distribution between striatum and globus pallidus (Kataoka et al., 2010). This in turn may be due to the fact that in TS, there are substantially fewer fast spiking GABA-ergic interneurons in the striatum that orchestrate neural oscillation; for effective sensory gating, one needs the capacity to sustain neural oscillations in the basal ganglia (Leckman et al., 2010b). Thus, it seems that relatively smaller number of these cells in the dorsal lateral striatum might be a key factor in the generation of tics. Several studies have shown that Clonidine, an α (2)-adrenoceptor agonist, is effective in relieving tics, and the mechanism of action is thought to be linked to clonidine's effect on inhibitory learning resulting from reduced noradrenergic activity (Katini et al., 2011). Further, a recent study in schizophrenia suggested that clonidine may exert beneficial effects through improving prefrontal cognitive function and inhibitory control (Oranje and Glenthoj, 2013). This paper reported on a double blind, placebo-controlled, randomized, cross-over study involving schizophrenia patients and normal healthy controls. They found that clonidine significantly increased percentage PPI in the patients compared with placebo, to such levels that it no longer differed significantly from the healthy controls. However, none of the dosages of Clonidine increased sensitization or influenced habituation. Thus, clonidine restored PPI in these patients which suggests that the clinical effectiveness of clonidine in ameliorating tics may be the result of specific effects on the sensorimotor gating mechanisms. In addition to the clinical relevance and the neurophysiological significance of the effect of Clonidine in TS, there may also be an opportunity to elucidate the genetic underpinnings of the pathophysiological abnormalities and the potential for individualized treatments in TS. In this regard, good clinical response to clonidine was recently reported in a TS patient with a well-defined pathological genotype, namely disruption of the IMMP2L gene (Katuwawela and Cavanna, 2012). Therapeutic response is often a function of the pathological genotype which can have profound implications for understanding both the pathology and response to therapy – which is particularly relevant in this case as IMMP2L is one of the few genes that has been recurrently disrupted in TS (Patel et al., 2011; Petek et al., 2001) and in each case the disruption halts the convergent transcription of IMMP2L across LRRN3, the gene located within intron 3 of IMMP2L on the opposing DNA strand (Clarke et al., 2012). Furthermore, LRRN3, a brain enriched neuronal transmembrane leucine rich repeat protein gene is localized within the genomic region most commonly duplicated in ASD (Maestrini et al., 2010; Pagnamenta et al., 2010) and LRRN3's closest relation LRRN1 is also duplicated in ASD
Letter to the Editor / Psychiatry Research 215 (2014) 494–496
(Davis et al., 2009), indicating that dose increases for these two closely related molecules are pathogenic for ASD and TS. The rub being that LRRN1 has a well established role in brain boundary formation during development and in restricting neuronal cell migration and mixing between brain compartments (Tossell et al., 2011). Moreover, ectopic over-expression of Lrrn1 in the chick results in the mixing of cells between brain compartments (Tossell et al., 2011). LRRN1 function in brain boundary formation appears certain to relate to an as yet unidentified ligand that regulates inter-neuronal affinity (Tossell et al., 2011). Competitive binding as it relates to inter-neuronal ligand based affinity is now a pathogenic theme in TS and ASD (Clarke et al., 2012). This pathogenetic model for TS integrates all five of the genes uniquely disrupted in TS within a single competitive neuropathogenetic chain of events comprising the full complement of known neurexin post-synaptic cell adhesion ligand gene families. Interestingly, LRRTM3, another neuronal leucine rich repeat (LRR) transmembrane closely related to LRRN3 has been linked with ASD and TS through the neurexin connexus (Clarke et al., 2012). LRRTM3 is just one of the full complement of neurexin post-synaptic cell adhesion ligand gene families now implicated in TS (Clarke et al., 2012). Balance within the neurexin trans-synaptic connexus appears essential in regulating neuronal circuitry as it pertains to TS and ASD. In turn, the imbalance in neuronal circuitry associated with an imbalance in the neurexin connexus (Clarke et al., 2012) may provide a by-pass to normal gating mechanisms. It is also of interest that LRRN3 and LRRTM3, two neuronal leucine rich repeat (LRR) transmembrane protein genes found associated with ASD are both found nested within introns of genes that have been repeatedly disrupted in TS namely IMMP2L and CTNNA3, respectively (NCBI Build 37.2, 2011) (Clarke et al., 2012). LRRTM3 and LRRN3 are related by virtue of their extracellular LRR ligand binding domains. An improved understanding of LRRN ligand binding is likely to have a profound impact on understanding the molecular basis of ASD and TS pathology as LRRN3's closest relation LRRN1 is known to regulate boundary formation within the developing brain, restricting neuronal cell migration/ mixing between compartments, presumably as a direct function of intercellular ligand affinity (Tossell et al., 2011). Any relaxation in the specificity of neuronal connections associated with the upregulation of LRRN3 or its ligand(s) or any of the neurexin cell adhesion ligands implicated in the TS model (Clarke et al., 2012) may permit aberrant circuitry formation between compartments which in turn may provide a by-pass to normal gating mechanisms. It may well be that neuronal cell adhesion ligands have multiple overlapping roles in terms of signal transmission/maintenance and regional connectivity resulting in different phenotypic presentations, all of which may have sensorimotor gating abnormalities but mediated through different neurotransmitter circuitry. In this regard, previous studies in animals and humans have shown that experimentally-induced PPI deficits can be removed by the administration of antipsychotic agents and that PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable (Swerdlow et al., 2006). These investigators observed that PPI disrupted by the norepinephrine alpha-1 agonist, cirazoline was prevented by clonidine but not haloperidol while PPI disrupted by the D1/D2 agonist apomorphine was prevented by D2 antagonist haloperidol but not clonidine. Such differential neurochemical pathways may provide valuable clues into the pathogenesis of different clinical manifestations or disorders arising from similar pathogenetic processes involving PPI. Further, sensorimotor gating abnormalities have been reported in a number of developmental and psychiatric disorders although there is debate as to whether the diversity of disorders exhibiting deficient PPI represents diagnostic overlaps or
495
comorbidities (Geyer, 2006). Nevertheless, it is, thus, not inconceivable that the ability of clonidine and other tic-suppressant medication to enhance short interval, “automatic” gating reflects a mechanism that is relevant to their therapeutic properties in TS and other related psychiatric disorders. Further, it appears that the neurophysiological deficits such as PPI abnormalities arising from abnormalities in circuitry formation during development may be mediated through specific gene involvement and clonidine restores this, possibly via restoration of impaired prefrontal cortical functions in those patients where the relevant circuitry is involved. It could be argued that, if neurexin-ligand cell adhesion was instrumental in both signal transmission/maintenance and regional demarcation and connectivity during development, then copy number variation doseeffects of the ligands could affect either or both of the above events to different degrees based on the underlying genetic background resulting in different developmental outcomes. Findings built on previous work suggest that at least some genes expressed peripherally are relevant for central nervous system (CNS) pathology in the brain of individuals with TS (Gunther et al., 2012) but it is to be noted that correlations between microarray analysis of peripheral blood gene expression in Tourette syndrome may have no reflection on CNS pathology and provide no reliable indication as to the pathogenetic phenotype in these patients. We believe the neuropathogenetic model described by Clarke et al. (2012) provides a suitable framework for testing the underlying pathogenetic processes and development of new treatment strategies in TS and related disorders. In this regard, future studies are indicated using mouse models to elucidate the developmental effects of upregulation of LRRN3 and the response to clonidine.
References Bloch, M.H., Leckman, J.F., Zhu, H., Peterson, B.S., 2005. Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome. Neurology 65, 1253–1258. Bohlhalter, S., Goldfine, A., Matteson, S., Garraux, G., Hanakawa, T., Kansaku, K., Wurzman, R., Hallett, M., 2006. Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain 129, 2029–2037. Castellanos, F.X., Fine, E.J., Kaysen, D., Marsh, W.L., Rapoport, J.L., Hallett, M., 1996. Sensorimotor gating in boys with Tourette's syndrome and ADHD: preliminary results. Biological Psychiatry 1 (39), 33–41. Clarke, R.A., Lee, S., Eapen, V., 2012. Pathogenetic model for Tourette syndrome delineates overlap with related neurodevelopmental disorders including Autism. Translational Psychiatry 2, e158. Davis, L.K., Meyer, K.J., Rudd, D.S., Librant, A.L., Epping, E.A., Sheffield, V.C., 2009. Novel copy number variants in children with autism and additional developmental anomalies. Journal of Neurodevelopmental Disorders 1, 292–301. Eapen, V., Crncec, R., 2009. Tourette syndrome in children and adolescents: special considerations. Journal of Psychosomatic Research 67, 525–532. Fried, I., Katz, A., McCarthy, G., Sass, K.J., Williamson, P., Spencer, S.S., Spencer, D.D., 1991. Functional organization of human supplementary motor cortex studied by electrical stimulation. J. Neurosci. 11, 3656–3666. Geyer, M.A., 2006. The family of sensorimotor gating disorders: comorbidities or diagnostic overlaps? Neurotoxicity Research 10, 211–220. Gunther, J., Tian, Y., Stamova, B., Lit, L., Corbett, B., Ander, B., Zhan, X., Jickling, G., Bos-Veneman, N., Liu, D., Hoekstra, P., Sharp, F., 2012. Catecholamine-related gene expression in blood correlates with tic severity in Tourette syndrome. Psychiatry Research 200, 593–601. Hampson, M., Tokoglu, F., King, R.A., Constable, R.T., Leckman, J.F., 2009. Brain areas coactivating with motor cortex during chronic motor tics and intentional movements. Biological Psychiatry 65, 594–599. Katini, E., Cassaday, H.J., Hollis, C., Jackson, G.M., 2011. The normal inhibition of Associations is Impaired by clonidine in Tourette syndrome. Journal of the Canadian Academy of Child and Adolescent Psychiatry 20, 96–106. Kataoka, Y., Kalanithi, P.S., Grantz, H., Schwartz, M.L., Saper, C., Leckman, J.F., Vaccarino, F.M., 2010. Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals with Tourette syndrome. Journal of Comparative Neurology 518, 277–291. Katuwawela, I., Cavanna, A.E., 2012. Good response to clonidine in tourette syndrome associated with chromosomal translocation involving the IMMP2L gene. Journal of Psychiatry and Clinical Neuroscience 24, E17. Le Moal, M., Simon, H., 1991. Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiological Review 71, 155–234.
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Letter to the Editor / Psychiatry Research 215 (2014) 494–496
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Valsamma Eapen n, Philip Ward, Department of Infant, Child and Adolescent Psychiatry, Academic Unit of Child Psychiatry, University of New South Wales, South West Sydney, Sydney, NSW, Australia E-mail address: [email protected] (V. Eapen). Raymond Clarke Department of Human Genetics, Ingham Institute, School of Medicine, University of Western Sydney, Sydney, NSW, Australia Received 11 September 2012 12 September 2013 15 October 2013 Available online 23 October 2013
n Correspondence to: LI, Mental Health Centre, Liverpool Hospital, Elizabeth Street, NSW 2170, Australia. Tel.: þ61 2 96164364.
