Question

Histidine decarboxylase (Hdc) deficiency due to mutation was found to be a rare but highly penetrant cause of TS. Without this enzyme, Histidine can't be converted into the neurotransmitter Histamine. The Hdc-KO mouse model was created with the intention to understand how this lack of histamine might bring forth symptoms seen in Tourette's Syndrome. Importantly, the model did in fact generate stereotypies analogous to the tics found in TS, as well as an increase in striatal dopamine, supporting the dopaminergic hypothesis discussed prior. Regarding microglia in the striatum of these animals, there was found to be a reduced expression of the neuroprotective protein insulin-like growth factor 1 (IGF-1). While there is a reduction in neurotrophic support, there also seems to be a heightened microglial response to immune challenge in the Hdc-KO mice. This excessive activation of microglia and inflammation was only found local to the striatum, and not the motor cortex, further supporting the CSTC circuit dysregulation hypothesis of tic generation. Such a finding also suggests that individuals with TS are at greater susceptibility for negative inflammatory effects in the event of an infection such as streptococcal infections.

Answer 1

Histidine decarboxylase deficiency leads to Tourette's Syndrome symptoms due to the inability to convert histidine into histamine. The Hdc-KO mouse model supports the dopaminergic hypothesis and shows an increase in stereotypies and dopamine levels. Additionally, there is reduced expression of IGF-1 and increased microglial response in the striatum of these mice.

Step-by-step explanation:

Histidine decarboxylase (Hdc) deficiency due to mutation causes the inability to convert histidine into histamine, resulting in symptoms similar to those seen in Tourette's Syndrome. The Hdc-KO mouse model was created to understand how the lack of histamine leads to symptoms of TS. The model showed an increase in stereotypies and dopamine levels, supporting the dopaminergic hypothesis. In the striatum, there was reduced expression of insulin-like growth factor 1 (IGF-1) and increased microglial response to immune challenge, which indicates susceptibility to inflammation in TS individuals.

Histidine decarboxylase (Hdc) deficiency has been linked to Tourette's Syndrome (TS) through its role in histamine production. Mice models lacking this enzyme exhibit symptoms similar to TS, including increased striatal dopamine and heightened microglial response. Furthermore, there is evidence showing reduced expression of the neuroprotective protein insulin-like growth factor 1 (IGF-1) in the striatum, pertinent to the inflammation hypothesis in TS. This insight suggests a vulnerability in TS patients to inflammatory effects post-infection.