P1 B3 CTB Basal Ganglia and Movement Disorders 23-24 Slides PDF

Basal Ganglia and Movement Disorders Dr Mark Richards [email protected]. uk Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the...

Basal Ganglia and Movement Disorders Dr Mark Richards [email protected]. uk Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the main symptoms of Parkinson’s disease  Describe the pathological mechanisms of Parkinson’s disease and how the condition affects the control of movement  Outline the main symptoms of Huntington’s disease  Describe the pathological mechanisms of Huntington’s disease and how the condition affects the control of movement Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the main symptoms of Parkinson’s disease  Describe the pathological mechanisms of Parkinson’s disease and how the condition affects the control of movement  Outline the main symptoms of Huntington’s disease  Describe the pathological mechanisms of Huntington’s disease and how the condition affects the control of movement Control of voluntary movement Activity Supplement Excites Muscles via Primary the ary Motor Corticospinal and Motor Cortex and Corticobulbar Tracts Cortex Premotor Cortexes Activity Activity Excites Activity Excites the Excites the Basal Cortex the Ganglia Cortex Basal Thalam Modulation of output Ganglia Activity us (+ or -) Inhibits the Thalamus Circuitry of the Basal Ganglia Muscles via excitato Corticospinal and Substantia ry Nigra Pars Corticobulbar Tracts Cortex Compacta inhibitor excitato excitato excitato ry y ry ry Globus Thalamu Major Striatum Pallidus s Ventral input (Putamen inhibitor inhibitor and Internus Anterior/ y y nucleus Caudate Nucleus) and Lateral SNPR Nucleus Major inhibitor y output GPi tonically nucleus active Globus Pallidus inhibitor Subthalami y c Nucleus Externus C A I B lo ck 3 Reentrant Loops Are a Cardinal Bas al G anglia Principle of Basal Ganglia Circuitry Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the main symptoms of Parkinson’s disease  Describe the pathological mechanisms of Parkinson’s disease and how the condition affects the control of movement  Outline the main symptoms of Huntington’s disease  Describe the pathological mechanisms of Huntington’s disease and how the condition affects the control of movement Neurotransmitters of the BG Inputs and outputs of BG Major input from cortex to striatum/putamen Major output from Gpi to thalamus GPi tonically active Neurotransmitters of the BG INPUT: Glutamate from cortex OUTPUT: GABA through BG to thalamus Glutamate from thalamus to cortex Glutama Dopamine modulation te GABA https://www.clinicalkey.com/student/co from Substantia nigra ntent/book/3-s2.0-B978032379333900 Dopamin e 0122#hl0002184 Input to Basal Ganglia Major input from cortex is to the striatum Striatum consists of putamen and caudate nucleus Medium spiny neurons receive cortical input Glutamatergic synapses Modulated by dopamine from substantia nigra pc Glutamate signalling Glutamate activates AMPA and NMDA receptors, to excite the post-synaptic neuron via EPSPs AMPA – Na influx NMDA – Na & Ca influx Glu - glutamate VGLUT – vesicular glutamate Gln - glutamine transporter PAG - phosphate-activated SN - amino GLT/GLST acid transporter – Glutamate glutaminase SAT - amino acid transporter transporter Medium spiny neurons MSNs constitute around 95% of the striatal neuronal population and are the only projection neurons of the striatum. Each MSN has about 10,000 dendritic spines and is the spiniest neuron type in the brain. MSNs are intrinsically silent with low excitability. MSN activity is mainly triggered by cortical glutamatergic inputs, with dopamine providing crucial regulation. MSNs express the highest level of D1 https://www.clinicalkey.com/student/content/ receptors or D2 receptors in the brain. book/3-s2.0-B9780702073373000080#hl000 5134 Output from Basal Ganglia Output from GPi to thalamus GABAergic synapses Glutama Gpi is tonically active and te GABA receives excitatory inputs from STN Inhibition of thalamus to prevent unwanted movement GABA signalling GABA activates GABA receptors, to inhibit the post-synaptic neuron via IPSPs GABAA - chloride channels GABAB – metabotropic linked to K channels Glu - glutamate PAG - phosphate-activated VGAT – Vesicular GABA Gln - glutamine glutaminase transporter GAD – glutamic acid GAT – GABA transporter decarboxylase SN – amino acid transporter Disinhibition determines Basal Ganglia The output basal ganglia loop uses disinhibition to select motor activities Glutam ate GABA GPi tonically Dopami active C A I B lo ne Direct and indirect Logic P ck 3 uzzle pathways modulated https://ebookcentral.proquest.com/li b/warw/reader.action?docID=61753 by dopaminergic 87&ppg=998 Neuromodulation of BG input Substantia Nigra pars compacta Dopaminergic neurones project to striatum Innervation of striatal medium spiny neurones Dopamine acts as a neuromodulator Dopaminergic modulates indirect and direct pathways Dopamine facilitates movement through: MSN Stimulating the direct pathway Inhibiting the indirect pathway https://www.clinicalkey.com/student/content/book/ 3-s2.0-B9780323793339000122#hl0002184 Dopamine signalling Dopamine is recycled via reuptake into Dopamine synthesised the presynaptic terminals via dopamine from the amino acid transporter (DAT) Tyrosine in the presynaptic terminals Repackaged into vesicles via vesicular monoamine transporter Medium spiny neurons express either D1 or D2 receptors Dopamine receptors D1 receptors excite the direct pathway D2 receptors Inhibit the indirect pathway D1 D2 Dopamine facilitate s movemen Glutam ate GABA t https://www.clinicalkey.com/student/content/ book/3-s2.0-B9780702073373000080#hl000 Dopamin 5134 e https://www.clinicalkey.com/student/content/ book/3-s2.0-B9780323793339000122#hl000 Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the main symptoms of Parkinson’s disease  Describe the pathological mechanisms of Parkinson’s disease and how the condition affects the control of movement  Outline the main symptoms of Huntington’s disease  Describe the pathological mechanisms of Huntington’s disease and how the condition affects the control of movement Movement disorders Disruption of the BG circuitry can lead to movement disorders Hyperkinetic disorders Excessive involuntary movements etic Hyperkin = disorders Hypokinetic disorders Reduced a ctivity of Deficient voluntary movement G pi Bradykinesia Hypokine tic = disorders akinesia Increased activity of GPi Parkinson’s disease Huntington’s disease Parkinson’s disease Parkinson’s disease (PD) was first described in 1817 by James Parkinson Motor symptoms TRAP Tremor Rigidity Akinesia Postural instability Idiopathic in most cases, up to 10% can be familial: genetic mutations https://www.clinicalkey.com/student/conte nt/book/3-s2.0-B9780323793339000122# hl0002216 https://ebookcentral.proquest.com/lib/war w/reader.action?docID=6175387&ppg=1 Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the main symptoms of Parkinson’s disease  Describe the pathological mechanisms of Parkinson’s disease and how the condition affects the control of movement  Outline the main symptoms of Huntington’s disease  Describe the pathological mechanisms of Huntington’s disease and how the condition affects the control of movement Pathology – neuronal loss The substantia nigra pars compacta contains the cell bodies of dopaminergic neurons contributing to the nigrostriatal tract The substantia nigra is almost black in the adult brain due to the (A) Normal midbrain (in cross section) accumulation with a deeply pigmented substantia of neuromelanin as a by- nigra; product PD of dopamine is associated with (B) Pallor of the substantia nigra in a protein accumulation and case of PD. synthesis aggregation mitochondrial abnormalities neuronal loss in the substantia nigra https://www.clinicalkey.com/student/content/book/3-s2.0-B9780323531139000285 #hl0002825 https://ebookcentral.proquest.com/lib/warw/reader.action?docID=6175387&ppg=1 Pathology – Protein aggregation α-synuclein, an abundant lipid-binding protein normally localized to synapses. This protein is a major component of the Lewy body, which is the diagnostic hallmark of PD. α-synuclein is normally a soluble protein Aggregates are formed by insoluble fibrillary deposits Lewy bodies. The most common (A) On routine H&E-stained sections Lewy bodies appear as bright pink structures in the neuronal forms of familial PD cytoplasm, surrounded by a pale halo; (B) They are due to mutations can also be demonstrated by in the α-synuclein immunohistochemistry for alpha-synuclein gene protein, which is the main constituent. https://www.clinicalkey.com/student/content/book/3-s2.0-B9780323531139000285#hl000282 5 https://www.clinicalkey.com/student/content/book/3-s2.0-B9780443103216000138#hl000052 Pathology – Lewy bodies Progression of pathology through tracking presence of Lewy bodies Lewy body pathology begins in the medulla and olfactory bulbs, spreading progressively through six Braak stages to involve the pons, midbrain, limbic lobe, amygdala and neocortex Braak H. et al. (2003) Journal of Neural Transmission , 110:517. Neuronal cell death – protein aggregation Protein aggregates Ubiquitin-proteasome system Alpha synuclein forms aggregates: Lewy bodies Parkin protein implicated in Pore-forming complexes abnormal protein degradation thought to increase membrane permeability leading to Parkin genes are implicated in calcium influx – cell death some forms of familial PD Abnormal phosphorylation may be responsible for promoting CTB Blo ck 3 fibril formation of alpha Ageing synuclein CTB Blo ck 3 Cell Me ch Neuro Disease Neuronal cell death – mitochondria Mitochondrial andMutations ROSin α-synuclein, PARKIN, dysfunction DJ-1, PINK1, and LRRK2 proteins ATP depletion are associated with ROS Complex I inhibition generation, mitochondrial Excessive ROS damage, and apoptosis in production dopaminergic neurons. Mitochondrial dysfunction hypothesis supported by MPTP studies https://ebookcentral.proquest.com/lib/warw/reader.action?docID=6175387&ppg =1003 https://www.clinicalkey.com/student/content/book/3-s2.0-B97803235311390002 Neuronal cell death 2 3 mechanisms of cell death can interact Mitochondrial dysfunction Protein aggregation Abnormal UPS system A role for neuroinflammation Reactive gliosis Microglial activation Pathophysiology The degeneration of dopaminergic nigrostriatal cells leads to an imbalance in striatal output pathways Deficient activation of direct pathway Deficient inhibition of indirect pathway Results in overactivity of GABAergic pathways of indirect pathway Glutama and less activation te GABA of motor cortex https://www.clinicalkey.com/student/con Dopamin tent/book/3-s2.0-B97807020733730000 80#hl0005134 e https://ebookcentral.proquest.com/lib/w arw/reader.action?docID=6175387&ppg Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the main symptoms of Parkinson’s disease  Describe the pathological mechanisms of Parkinson’s disease and how the condition affects the control of movement  Outline the main symptoms of Huntington’s disease  Describe the pathological mechanisms of Huntington’s disease and how the condition affects the control of movement Huntington’s disease Hyperkinetic movement disorder Involuntary jerky, choreiform movements Age of onset usually >40 years Marked atrophy of striatum and cortex Inclusions present Caused by abnormal Normal hemisphere on the left compared with the hemisphere with Huntingtin gene Huntington disease on the right CAG repeats showing atrophy of the striatum and ventricular dilation. Inset, Intranuclear inclusions in neurons are highlighted by an immunohistochemical stain for ubiquitin. https://eurohuntington.org/ https://www.clinicalkey.com/student/content/book/3-s2.0-B9780323531139000285#hl0 002922 Learning Outcomes  Describe the major input and outputs of the basal ganglia  Describe the role of neurotransmitters in the control of movement by the basal ganglia  Outline the main symptoms of Parkinson’s disease  Describe the pathological mechanisms of Parkinson’s disease and how the condition affects the control of movement  Outline the main symptoms of Huntington’s disease  Describe the pathological mechanisms of Huntington’s disease and how the condition affects the control of movement Pathology Inclusions Excitotoxicity Formed from aggregates of abnormal huntingtin Transcriptional protein dysregulation Leading to: Mitochondrial dysfunction Oxidative stress https://www.clinicalkey.com/student/content/book/3-s2.0-B9780323531139000285#hl0002922 https://ebookcentral.proquest.com/lib/warw/reader.action?docID=6175387&ppg=1007 https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702073373000080#hl0005134 Pathophysiology Selective loss of medium spiny neurons in the striatum associated with the indirect pathway Loss of inhibition of involuntary movements Loss of striatal efferent connections lead to hyperactivity of dopaminergic neurons exciting the direct pathway Result: increased involuntary movement - Glutama te hyperkinesia https://ebookcentral.proquest.com/lib/w GABA arw/reader.action?docID=6175387&ppg Dopamin =1007 e https://www.clinicalkey.com/student/con tent/book/3-s2.0-B97807020733730000 Summary Disorders of the basal ganglia may imbalance the direct and indirect pathways resulting in either hyperkinetic or hypokinetic disorders Hyperkinetic disorders = Reduced activity of GPi ay Why m al n functio f the io on inhibit lamic subtha a deep s (vi Hypokinetic disorders = Increased activity of GPi nucleu mulation) s ti brain te the allevia s of om sympt on’s in s Park e? https://www.youtube.com/watch?v=Sb6YjAfB1H0&t=7s dis se a https://www.youtube.com/watch?v=mkGfxi23Zv0 https://www.youtube.com/watch?v=jy1IFJbMLF8&t Further Reading Recommended Reading: Physiology (Costanzo) Chapter 3 https://www.clinicalkey.com/student/content/book/3-s2.0-B97803237933 39000122#hl0002184 Neuroscience: Exploring the Brain (Bear) Chapter 14 https://ebookcentral.proquest.com/lib/warw/reader.action?docID=61753 87&ppg=995 Robbins & Cotran Pathological basis of disease (10th Ed) Chapter 28 https://www.clinicalkey.com/student/content/book/3-s2.0-B97803235311 39000285#hl0002813 Acknowledgement to Prof Richard Tunstall for content used in this presentation