Neurochemistry of Tourette's Syndrome

Gilles de la Tourette
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Tourette's syndrome is a neurological disorder that
has been around since 15th century. However, it was not until 1885
that the disorder was characterized by Gilles de la Tourette.

Given its complex nature, it’s likely that Tourett's Syndrome involves a dysfunction in more than one neurotransmitter in the movement-related brain circuits however, since dopamine is a major player in the control of motor function, temporal processing, reward learning and response inhibition, the proposed dopaminergic hypothesis for Tourette's Syndrome should be further investigated.[1] Research suggests that dopamine neurotransmission may be the pathological abnormality at the level of the cortico–striato–thalami–cortical (CSTC) circuit however a primary defect has not yet been localized to the striatum, palladium, thalamus or cortex.[2] Factors contributing to abnormal dopamine neurotransmission include: supersensitive dopamine receptors, dopamine hyper-innervation, abnormal presynaptic terminal function or excess dopamine release.[1]

1. Cortico–Striato–Thalamo–Cortical Circuit

The basal ganglia are defined as discrete anatomical sets of neurons that modulate movement and they include the striatum (Caudate and Putamen), globus pallidus(GP), substantia niagra(SN) and subthalamic nuclie (STN). Despite general agreement that these structures are involved in Tourette's Syndrome pathophysiology, the exact neural mechanisms involved in the clinical manifestations of Tourette's Syndrome remain unknown. The advancements of knowledge regarding the functional anatomy of basal ganglia circuits and the fundamental importance of dopamine modulation on these circuits provide a basis for the hypotheses of dopamine related basal ganglia dysfunction in Tourette’s syndrome. [3] This section includes an overview of how the basal ganglia work to turn movement on or off in response to input from higher areas of the brain.

Schematic of the CSTC Circuit
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The direct (GO) pathway is generated by the cortex, which excites
the striatum and inhibits the GPi. This then causes the disinhibition of the
thalamus and thus allows for the excitation of the motor cortex; ultimately
resulting in a desired movement. The indirect (STOP) pathway generated
by the cortex leads to the activation of the STN, increasing the excitation of
GPi and inhibiting thalamo-cortical output, reducing the activation of the motor
cortex resulting in a cessation of a movement (see text for details).

The striatum receives excitatory glutamatergic input from virtually all regions of the cerebral cortex when a decision to move is made in these higher centres. The increase in the excitatory neurotransmitter input on the heads of the dendritic spines of medium spiny neurons (MSN) in the striatum increases their activity. In addition to the cortical input, the striatum also receives input from dopaminergic neurons of the SNpc (pars compacta). The dopamine input to the MSN of the striatum, however, terminates largely on the shafts of their dendritic spines, where it is a positioned opportunistically in order to modulate transmission from the cortex to the striatum. Since neurotransmission is mainly dependent on the type of receptor involved, the dopamine receptors have been grouped into two distinct families based on their activity on adenyl cyclase (AC) in response to dopamine agonists. The D1 receptors, found in the direct (Go) pathway of the striatum, are thought to stimulate AC activity and may increase the response of striatal neurons which project to the internal segment of the GP after cortical input. On the other hand the D2 receptors found in the indirect (Stop) pathway are thought to inhibit AC activity and may decrease the effect of cortical input to striatal neurons that project to the external segment of the GP.[3] Since the MSN in the striatum contain the inhibitory neurotransmitter GABA they are inhibitory to their targets, weather it be the internal or external segments of the GP. [3]

1.1 Direct Pathway:

With projections to the GPi and SNpr, as the striatum is stimulated, it causes an increase in the GPi and SNpr firing activity. So in a sense, now that striatal neurons are firing more rapidly, they send increased inhibitory signals, via GABA and substance P, to the GPi and SNpr. Under normal conditions, the GPi and SNpr neurons function to form an inhibitory synapse with the VA/VL nucleus of the thalamus via GABA. However, since GPi and SNpr are receiving more inhibitory signals from the striatum now, this causes the inhibitory signal to the thalamus to be dampened; also known as disinhibition. Now that the thalamus is disinhibited, it can send its excitatory signals, via glutamate, to the cerebral cortex, which ultimately results in a desired movement. [1]

1.2 Indirect Pathway:

Stimulatory signal from the cortex reach the striatum, via the neurotransmitter glutamate, as seen in the direct pathway. Like the previous pathway, the striatum also has inhibitory output to the GP, however in this pathway, it synapses onto the external segment, and uses the neurotransmitters GABA and enkephalins. The normal role of the GPe is to inhibit the STN via GABA. Since the GPe is receiving more inhibitory signals from the striatum, it is no longer able to inhibit the STN; so there is less inhibition of the STN. So now STN neurons become more active and are able to send more stimulatory signals to the GPi via glutamate. As seen previously in the direct pathway, the GPi normally functions to inhibit the VA/VL nucleus of the thalamus. So with increased inhibitory flow from the GPi to the thalamus, there will be decreased excitatory flow to the cortex.[1]

2. Dopamine Hypothesis

Dopamine, mainly in the CSTS pathway, has a vital role in subcortical neurotransmission. As such, hypotheses involving dopamine in Tourette’s syndrome revolve at the level of the striatum. Dopaminergic inputs coming into the striatum from pars compacta of the SN play an important role in coordinating the output of the striatum. Here, the activation of D1 receptors in the direct (Go) pathway lead to an enhanced thalamocortical stimulation that enhances movement, while activation of D2 receptors in the indirect (Stop) pathway reduce thalamocortical activity and subsequently diminish movement. Excess dopamine release in this context is believed to be influencing the tic behaviours that are characteristic of Tourette’s Syndrome. To date, these hypotheses have suggested supersensitive dopamine receptors, hyperinnervation of dopaminergic neurons, abnormal presynaptic terminal function and excess dopamine release. Currently however, more evidence is leaning toward the excess dopamine release hypothesis, as the number of supporting clinical studies increase. The recent studies that show support for the excess dopamine hypothesis will be further discussed here.

A strong support for the excess dopamine hypothesis comes from the results of clinical trials that show the efficacy of D2 dopaminergic receptor blockers in suppressing motor tics. A small controlled study conducted by Borrison et al compared haloperidol, fluphenazine, and trifluoperazine which are all traditional antipsychotics and found a strong correlation between increased dosage and the suppression of tics. While haloperidol was associated with more sedation and side effects, fluphenazine was found to be the most tolerated. Furthermore, Fluphenazine was reported as the safest of all three in long term use, as no case of tardive dyskinesia was observed in a follow up study of patients that were treated for at least a year. Tardive dyskinesia, a disorder resulting in repeated involuntary body movements, is known to be associated with the long term use of traditional antipsychotics.[4]

One of the critical steps in pre-synaptic Dopamine production is the transporting of the neurotransmitter Dopamine into the synaptic vesicles. This is achieved by the vesicular monoamine transporter 2 (VMAT2), an integral membrane protein that transports monoamines, mainly dopamine, from the cytosol into the vesicle. In the context of excess dopamine release hypothesis, this transporter was seen as a good target to decrease excess dopamine release. Tetrabenazine, marketed under the name of Nitoman in Canada, achieved this effectively by working as VMAT inhibitor. Tetrabenazine promotes the early degradation of monoamines, and inhibits their transport into synaptic vesicles to overall decrease dopamine release from the pre-synaptic neuron. Another strong evidence for the validity of the excess dopamine hypothesis came from a 2007 study where long term tolerability of Tetrabenazine was asssed by analizing patients treated with the drug between 1997 and 2004. An efficacy response rating of 1 or 2 (marked reduction in abnormal movements/tics) was maintained in a significant number of patients. The researchers concluded that decreasing dopamine release in patients with hyperkinetic movement disorders is strongly correlated with decreased tic behaviors, supporting the excess dopamine hypothesis. [5]

As perhaps controls to the studies mentioned above, the correlations above were confirmed by Anderson and his team by reporting an increase in tics following the withdrawal of neuroleptics. Furthermore, they also saw an increase in tic behaviours following the exposure to drugs such as L-dopa and cocaine, which both can act to increase central dopaminergic activity. In general, the dopamine hypothesis, specifically the excess dopamine release hypothesis, suggests an increased signal transduction of the neurotransmitter dopamine in the CSTS pathway ultimately leading to the tic behaviours observed in Tourette’s patients. [6]

2.1 Elevated Intra-synaptic Dopamine Release

Intrasynaptic dopamine levels are modulated by two mechanisms: tonic and phasic dopamine transmission. While tonic transmission occurs independently of neuronal activity and refers to the small amounts of dopamine released that determine the long term dopamine homeostasis, phasic release refers to the spike-dependent release of the transmitter from dopaminergic neurons themselves. [1]

2.1 a Phasic Vs. Tonic Release

Tonic dopamine is the average amount of dopamine found extracellularly over a long range of time. Its found in low concentrations, and determines the long term dopamine homeostasis including the regulation of post synaptic receptors. The regulation of post synaptic receptors has an inverse relationship with tonic dopamine levels, as a reduction in tonic dopamine will trigger the upregulation of postsynaptic dopamine receptors. Tonic dopamine can be regulated by autoreceptors and dopamine transporters active in the synapse. Here in the synapse, hyperactive transporters resulting in increased reuptake could lead to lower tonic dopamine levels. This in turn would trigger the upregulation of post-synaptic receptors in a compensatory mechanism. [7] Several papers have pointed to abnormalities in tonic dopamine levels, suggesting a lower tonic release. One of these include the imaging studies by Singer et al that reported increased number of presynaptic transporters in post mortem striatum, suggesting lower tonic dopamine. The suggested lower tonic dopamine levels ties back to the excess dopamine release hypothesis due to the compensatory mechanism previously mentioned. Lower tonic levels of dopamine trigger the upregulation of post-synaptic receptors, increasing the overall sensitivity of the neuron. Once spike-dependent (phasic) release occurs, the hypersensitive neuron undergoes increased activation, subsequently activating the CSTC pathway excessively. The suggested possibility of hyperinnervated dopaminergic neurons along with the increased synaptic release of dopamine following its hyperactive reuptake add to the increased phasic release of dopamine.[1]

Life with Tourette's
An inspirational video of children with Tourette's Syndrome

1. Martino, Davide. "Neurochemistry of Tourette's Syndrome." Tourette syndrome. Oxford: Oxford University Press, 2013. pp. 276-300. Print.
2. Yoon D Y., Gause C D., Leckman J F., Singer H S.(2007). Frontal dopaminergic abnormality in Tourette syndrome: A postmortem analysis. Journal of the Neurological Sciences, Vol.255:1, pp. 50-56.
3. Mink J.W. (2006). Neurobiology of basal ganglia and Tourette syndrome: basal ganglia circuits and thalamocortical outputs. Advances in Neurology, Vol. 99, pp. 89-98
4. Scahill L., Erenberg G., Cheston M., Budman C., Coffey B.J, Jankovic J., Kiessling L., King R.A, Kurlan R., Lang A., Mink J., Murphy T., Zinner S., Walkup J. (2006). Contemporary Assessment and Pharmacotherapy of Tourette Syndrome. The Journal of the American Society for Experimental NeuroTherapeutics, Vol.3, pp.192-206
5. Kenney C.,Hunter C.,Jankovic J. (2007). Long-term Tolerability of Tetrabenazine in the Treatment of Hyperkinetic Movement Disorders. Movement Disorders, Vol. 22:2, pp.193-197
6. Leckman J.F., Bloch M.H, Smith M.E., Larabi D., Hampson M. (2010). Neurobiological Substrates of Tourette’s Disorder. Journal of Child and Adolescent Psychopharmocology, Vol. 20:4, pp. 237-247
7. Grace A.A. (1991) Phasic Versus Tonic Dopamine Release and the Modulation of Dopamine Responsitivity A Hypothesis for the Etiology of Schizophrenia. Neuroscience , Vol. 41:1, pp. 1-24

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