Cheryl Richards edited Pathophysiology.md  about 8 years ago

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In a rodent model removing about half of the cholinergic interneurons in the dorsolateral striatum produced increased fragmented grooming behavior in response to a repeated unpredictable acoustic startle stimuli and increased repetitive sniffing in response to D-amphetamine challenge \citep{25561540}. Ablation in the dorsomedial striatum did not produce similar deficits. None of the experimental conditions produced a change in prepulse inhibition.  A detailed review \cite{26275849} describes the involvement of histaminergic modulation of striatal function by the tuberomamillary nucleus of the hypothalamus. The roles described for histamine are that it suppresses both the thalamic and cortical drive to medium-spiny projection neurons (MSNs), modulates thalamostriatal synapses resulting in a facilitation of thalamic input, and suppresses lateral feedback inhibition. The authors suggest that during wakefulness and increased attention the striaum will be more responsive to thalamostriatal input and feedforward inhibition will predominate(?). The role of histamine in TS was discussed in terms of a rare mutation involving histamine synthesizing enzyme histidine decarboxylase in one TS human adult and decreased prepulse inhibition of startle responses and an increase in a variety of stereotypies which decreased in response to histamine infusion or use of haloperidol. Effects were thought to occur as a result of the histaminergic control of the lateral GABAergic inhibitory connections between MSNs and ongoing research on histaminergic treatment for TS was discussed.  A collaborative genetic study \citep{25735483} demonstrated an association of TS with 33 genes related to glycolysis or glutamine metabolism. None of the individual genes would have survived correction for multiple testing and the results were consistent with a combined effect of many genetic variants of small effect. These results narrow the hunt for genes that may contribute to the development of TS and they also suggest a new direction for future electrophysiological, imaging and pharmacological studies.   Transcriptome analysis of the human striatum in Tourette syndrome \citep{25199956} | This important study follows up on the autopsy results from the Vaccarino lab by comparing RNA transcripts from the basal ganglia of 9 TS and 9 matched control subjects. The most strongly associated set of downregulated transcripts involved striatal interneurons, consistent with the autopsy studies. The leading set of upregulated transcripts involved immune-related genes even though none of the TS subjects met the diagnostic criteria for pediatric autoimmune streptococcal-associated neuropsychiatric disorders or pediatric acute onset neuropsychiatric syndrome. There was a lack of overlap between the results obtained in the present study using brain tissue and previous studies using blood samples. The authors conclude that their results "strongly [implicate] disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction."