Parkinson's Disease: Pathways

Before discussing Parkinson's as a disease I must first explain the role of dopamine specifically in movement more so than memory but memory will come into it a little later and will make sense if you remember back to the synaptic plasticity posts.

Dopamine is an important biogenic amine present in the hippocampus but most the dopaminergic are most abundant in the pars compacta of the substantia nigra. This area of the brain stem is a collection of nuclei rich with melanin which is why it appears black (this is also why the retina is black). Anyway these dopaminergic neurons project to all over the brain especially the hippocampus and the rest of the limbic system in the mesolimbic pathway, this pathway controls an animals reward pathway so high dopamine in this pathway is a good thing. The mesocortical pathway projects to the dorsolateral prefrontal cortex which is involved in higher brain function including emotional control, motivation and higher cognitive function, so as you might expect, more is better but regulation still needs to be tight, interestingly this pathway begins at the ventral tegmental area as does the mesolimbic pathway and this area is dopaminergic and very near the substantia nigra . Another other main pathway for dopamine is the nigrostriatal pathway. This is the pathway from the substantia nigra pars compacta to the striatum.

The nigrostriatal pathway consists of two sub-pathways, the direct and indirect, The direct pathway is responsible for facilitating movements that have been instigated, so movements we want, whether it be kicking a ball or unconsciously retracting the arm after touching a hot kettle. The direct pathway begins in the substantia nigra and the dopaminergic neuron enters the putamen and then the caudate nucleus where it synapses with GABAergic neurons and substance P neurons which innervate the globus pallidus internal segment and the substantia nigra pars reticularis. The GABA and substance P neurons contain D1 dopaminergic neurons in the post synaptic membrane which are excitatory through the activation of adenylate cyclase and therefore cAMP and also increase phospholipase C level which leads to calcium release and therefore an action potential.

Activating the GABA receptor leads to an inhibition of GABA neurons in the globus pallidus internal segment and pars reticularis. These GABA neurons usually innervate the ventral anterior and ventrolateral nuclei in the thalamus. These nuclei signal to the motor cortex to say it is okay to make the movement which the cortex turns into movement. So at rest the GABA neurons from the globus pallidus and pars reticularis inhibit the thalamus to stop movement. But in initiating movement the GABA neurons are inhibited by the GABA neurons from the striatum that dopamine activated. Thus allowing the thalamic neurons to signal to the cortex via glutamate. It is in effect inhibition of an inhibition, this is known as disinhibition.

This video explains the direct pathway in basic terms quite well

So far this is the best diagram I have found to explain it but it all takes some getting used to.

The indirect pathway still has glutamate entering the striatum which allows GABAergic neurons to fire to inhibit the globus pallidus external segment preventing it from releasing GABA to the sub-thalamic nucleus meaning it is active to release glutamate to the globus pallidus internal segment. This activates it to release GABA to inhibit the ventral tier nuclei so the motor cortex cannot initiate movement. Dopamine inhibit this pathway by binding to D2 receptors in the striatum to stop GABA release to the external segment meaning this is active to inhibit sub-thalamic nucleus via GABA. This means no glutamate release to the internal segment meaning it cannot release GABA to the thalamus so it is not inhibited and therefore can signal to the motor cortex allowing movement to be initiated.

In Parkinson's disease these pathways are defective due to a loss of dopaminergic neurons in the substantia nigra pars compacta, meaning that the GABA neurons in the direct pathway have the D1 receptors not being activated by dopamine so the GABA cannot be released to inhibit the internal global pallidus so the thalamus is not disinhibited and so no movement occurs. The lack of dopamine disinhibits the indirect pathway so movements are inhibited. This is akinesia, a serious lack of movement and difficulty initiating movement.

One of the main symptoms of early Parkinson's is a resting hand tremor, treating Parkinson's by increasing dopamine rarely fixes this symptom suggesting it is not directly related to the loss of dopamine. It has been shown that serotonin deficiency in the red nucleus could be the cause or contributing factor to the resting tremor, but the truth is, as of yet we are not sure what the cause is. Patients also often have an isometric tremor and this can be explained because the reduction in dopamine makes it difficult to recruit motor units to perform a movement, this is hypometria and the body attempts to correct this by multiple bursts of activity in the basil ganglia to increase muscle activity, but the bursts will cause a tremor as the movement is being executed because the movement is not flowing but appearing in bursts of activity. In a way it is like watching a movie by rapidly pressing play and pause.

That is about it for pathways and their relations, it can be a bit to get your head round or you'll be a lucky one that gets it straight away, but if not, read over it a few times whilst following the diagrams and it will become clear.