Behavioral and stereological characterization of Hdc KO mice: Relation to Tourette syndrome

Abstract

A premature termination codon in the human histidine decarboxylase (Hdc) gene has been identified in a family suffering from Guilles de la Tourette syndrome (GTS). In the current study we investigated if mice lacking the histamine producing enzyme HDC share the morphological and cytological phenotype with GTS patients by using magnetic resonance (MRI) and diffusion tensor imaging (DTI), unbiased stereology and immunohistochemistry. Behavior of Hdc knock-out (Hdc KO) mice was assessed in an open field test. The results of stereological, volumetric and DTI analysis measurements showed no significant differences between control and Hdc KO mice. The numbers and distribution of GABAergic parvalbumin or nitric oxide-expressing and cholinergic interneurons were normal in Hdc KO mice. Cortical morphology and layering in adult Hdc KO mice were also preserved. In open field test Hdc KO mice showed impaired exploratory activity and habituation when introduced to novel environment. Our results indicate that Hdc deficiency in mice does not disturb the development of striatal and cortical interneurons and does not lead to the morphological and cytological phenotypes characterized by humans with GTS. Nevertheless, histamine deficiency leads to behavioral alterations probably due to neurotransmitter dysbalance on the level of the striatum.

Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development

“…The striatum is the main input nucleus of the basal ganglia, which exhibits extensive modulation by histamine in adulthood (Doreulee et al, 2001;Ellender et al, 2011;Castellan Baldan et al, 2014;Bolam and Ellender, 2016;Rapanelli et al, 2017a), and much evidence points to alterations in cortico-striatal-thalamo-cortical loops in Tourette's syndrome (Felling and Singer, 2011;McNaught and Mink, 2011). A series of in vivo studies using mice with reduced brain histamine levels, either through gene KO (Castellan Baldan et al, 2014;Abdurakhmanova et al, 2017) or acutely through chemogenetic manipulation of histaminergic neurons (Rapanelli et al, 2017a,b), have shown that this can recapitulate some key symptoms (e.g., increases in repetitive behaviors) as a result of changes in striatum. However, these studies were focused on adult animals, which limits our understanding of histamine's role during early striatal development as well as in relation to neurodevelopmental disorders.…”

Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine‐deficient mice

“…Indeed, standard open field test actually measures forced exploratory activity and represents the net result of two competing behavioral programs: exploration and stress‐induced defensive behavior . Previously we found no indication of increased anxiety in the novel open field in Hdc KO mice and in this study blood corticosterone levels after open field test were similar in Hdc WT and KO mice, thus pointing against increased anxiety and stress in Hdc KO mice . In addition, histamine‐deficient mice displayed increased numbers of body/head/forepaw shakes, further indicating an increase in stereotypic behavior or behavioral complexity, rather than enhanced escape behavior.…”

“…Hrh3 is involved in differential modulation of mRNA levels of striatal opioids, dyorphin and enkephalin. 11,12 Open field behavior, including general locomotion and rearings of Hdc KO mice has been described previously, but results have been inconsistent 4,[13][14][15][16] (see Table S1). Stereotypic behavior in Hdc KO mice has been quantified previously after treatment with high amphetamine doses, which induced immobility and focused sniffing in animals.…”

“…13,29 On the other hand, both young (2-5 months old) and older (12-14 months old) Hdc KO mice on C57Bl/6J background were hypoactive upon the exposure to novel environment during lights-on phase, while in our previous and current study, Hdc KO mice tested during lights-off phase were not hypoactive. 14,15 The contradictory results might be due to combination of two factors: first, different background strain (129Sv vs C57Bl/6J) and second, time of the testing (light vs dark phase).…”

“…In our previous study we found decreased rearing time and frequency in Hdc KO mice, while in the current study and in the study of Castellan Baldan et al frequency of rearing quantified manually by the observer were unaltered in Hdc KO mice. 4,14 In the first study we used an infrared beam detection system that counts rearings as breaks of the beam positioned at a the certain height above the bottom of the arena, while in the other studies rearings were identified visually by the observer. Therefore, rearing in Hdc KO mice might be of the same frequency, but lower in amplitude and duration and may be associated with increased repetitive or stereotypic behavior.…”