Lecture 9 Parkinsons disease Bradykinesia: Slowness of movement Pathology: Loss of dopamine producing cells from Substantia Nigra Pars

s Compacta. Treatment: Replace dopamine Lewy Bodies: are cytologic hallmark of PD Lew Bodies are an accumulation of Alpha synuclein in the nuclie of SNpc neurons Similar aggregation in cerebral cortical neurons has been associated with dementia. Basal Ganglia is composed The Striatum is composed of o Caudate o Putamen o Ventral Striatum Globus Pallidus (release GABA) o Internal: Sends axons to Thalamus o External: Sends axons to Subthalamic Nucleus Substantia Nigra and the Subthalamic Nucleus are seen as accessory nucleus of the Basal Ganglia. Substantia Nigra Pars Compacta: Releases Dopamine their axons terminate in the Striatum. Substantia Nigra Pars Reticulata: Releases GABA as a neurotransmitter and send axons to the thalamus. All cortical output is excitatory The Striatum is made of Medium Spiny Neurons which are GABAergic (release an inhibitory response) Direct Pathway (Go Pathway) Cortex sends excitatory signal to the Striatum which then sends an inhibitory signal to the Globus Pallidus Internal. The Globus Pallidus usually sends an inhibitory signal to the Thalamus. So when the Striatum is activated the Globus Pallidus is inhibited. This inhibition of what would have lead to an inhibitory signal send to the thalamus, leads to increase spike rate of the thalamus. Cortex Striatum Gpi Thalamus. Indirect Pathway (No-Go Pathway) Cortex sends excitatory signal to the Striatum which sends and inhibitory signal to the Globus Pallidus External (which sends an inhibitory signal to the Subthalamic Nucleus) Since the Striatum is inhibiting an inhibitory signal this leads to increase activity of the Subthalamic Nucleus which then sends an excitatory signal to the Globus

Pallidus Internal which then sends an inhibitory signal to the Thalamus, which leads to the suppression of an activity (movement). Corte Striatum Gpe Subthalamic Nucleus Gpi - Thalamus So, a particular motor program requires the cortex to activate the Go pathway for that movement and inactivate the No-Go pathway for that same movement. At the same time the No-Go pathway for competing movements has to be turned on. That means the corticostriatal synapses must be trained. For a specific situation requiring a specific movemtn, a set of Go pathway neurons must be active, the No-Go pathway for that same movement must be quiet and the No-Go pathway pathway for competing movements must also be active. Dopamine release from Nigrostriatle axons is the method used to train synapses. Now in Parkinsons we have degeneration of Nigral Neurons(SNc) This leads to increase in Excitability of STN and Gpi Increased inhibition of Thalamus Decreased Excitation of motor cortex This explains the weak movements and lack of movemnts in PD patients Dopamine released by volume neurotransmission from nigrostriatal axons strengthens GO pathway synapses that are active but weakens no-GO pathway synapses. This happens because dopamine works at different receptors in the two pathways (D1 receptors predominantly in the direct, GO pathway and D2 receptors in the indirect, noGO pathway). This is seen as a way of instructing GO pathway synapses the movement they produced was very rewarding and of instructing no-GO pathway synapses they tried to suppress a perfectly good movement. Failure to release dopamine is viewed as throwing the balance of activity to a pathological increase in activity of the indirect, no-GO path. The result, then, is a poverty of movement (akinesia) and weak movements (bradykinesia). Tremor is much harder to explain by this model; it is thought to arise from rhythmic activity in the system. Causes Aging: normal aging is associated with decline in dopaminergic neurons in SNpc Primary Features Bradykinesia Resting Tremor Cogwheel Rigidity Treatment: replace the deficiency of Dopamine in Basal Ganglia Dopamine does not cross the BBB, so we give precursor Levodopa A lot of Levodopa is converted to dopamine before it crosses the BBB by Dopamine Decarboxylase. So we need to also give Dopamine Decarboxylase Inhibitor (Carbidiopa)

Dopamine Agonist such as (Pramipexole, Ropinirole) are D2 dopamine agonist. By binding to D2 receptors on striatal neurons of the Indirect pathway, these drgus replace the dopamine that would have been released from SNpc axon terminals. Anticholinergics: For normal motor or muscle control, the effects of acetylcholine and dopamine need to be carefully balanced. When dopamine levels are low (as they are in people who have Parkinson's disease), a chemical imbalance results, causing symptoms such as tremor and rigid muscles. Anticholinergic medicines decrease levels of acetylcholine to achieve a closer balance with dopamine levels. Catecho-O-Methyl Transferase Inhibitors(Entacapone, Tolcapone): imipair catabolism of Levodopa (prolong half life) MAO-b is a mitochondrial enzyme (outer membrane of mitochondria) that breaks down monoamines in the cytosol of axon terminals. Dopamine (and norepinephrine and serotonin) are monoamines. Blocking MAO-b, therefore, increases the concentration of dopamine in the terminal and in synaptic vesicles. So we use MAO-b Inhibitors to increase number of dopamine in terminal. Deep brain stimulation has become the go-to therapy when levodopa fails. Electrodes implanted into the subthalamic nucleus are particularly effective in relieving the symptoms of PD. You should appreciate this effectiveness of DBS to the subthalamic nucleus does not make much sense if the standard model of PD is accepted; after all, it is over-excitation in this nucleus that is thought to produce bradykinesia and poverty of movement. Clearly we are missing something and as soon as we figure out what that is we will know a great deal more about the basal ganglia and how to treat diseases of the basal ganglia Levadopa along with Carbidiopa: brings in precursor (levodopa), and blocks Dopamine Decarboxylase from turing the precursor into dopamine before crossing BBB. Dopamine Agonist: Act like Dopamine. Anticholinergics: Helps bring back balance of Ach and Dopamine. MAO-b Inhibitors: Blocks MAO-bs from breaking down dopamine Catecho-O-Methyl Transferase Inhibitors: Prevents catabolism of Levodopa DBS: Stimulate Gpi, and Subthalamic Nucleus PREVIOUS EXAM QUESTIONS ON LECTURE 1. Which system of neurons in the basal ganglia is over excited in PD ( be sure to go from input to output in the basal ganglia circuit to describe this over excitation. a. The Indirect (NO-GO) path is over-excited by cortical inputs; these are striatal neurons that innervate GPe and, by inhibiting these neurons, drive the subthalamic nucleus to excite Gpi. With that Gpi excitation thalamic neurons are suppressed and voluntary movements become rare and weak. The same over-excitation turns on brainstem reticular neurons or

induces an unnatural rhythmic activity in basal ganglia to produce tremor and hyper reflexia. 2. One model for the intracellular mechanism for Parkinsons disease suggests dopamine, itself, is toxic when the Vesicular Monoamine Transporter cannot pump it into vesicles. Dopamine builds up, gets broken down and produces a toxic fragment. Thats the model. There is a very good reason to think that model is wrong, and it has to do with the most common treatment for PD. Tell us how the treatment for PD indicates to us that increased cytoplasmic levels of dopamine are not toxic to dopamine neurons. a. Levodopa treats not only the symptoms of PD but also works to delay the progression of the disease. 3. What leads us to conclude that drug therapy with levodopa and carbidopa not only treats the symptoms of PD but also delays the degeneration of dopamine neurons? a. Even after patients are taken off moderate or high dose of these drugs their symptoms are not nearly as severe as those of patients who received placebo. 4. In the old days which is to say before any of you were born surgical intervention for PD included pallidotomy and subthalamotomy. What is the surgical treatment of choice these days? a. DBS the implantation of stimulating electrodes into the STN and Gpi. OTHER SIDE NOTES Parkinsons has a Resting Tremor Hypokinetic Symptoms: Bradykinesia Hyperkinetic Symptoms: Dystonia