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Physiology of the Basal Ganglia and Cerebellum Thomas C. Westfall Important Things to Know About Striatal Outputs • What happens when we excite the outputs from the striatum via the direct and indirect pathways • What happens when we increase the neuronal firing of dopamine neurons (the nigral-striatal pathway) • What happens in Parkinson’s Disease when we decrease dopamine activity Cotransmitters Involved in Striatal Output DIRECT PATHWAY: Striatum to Globus Pallidus pars interna (GPi)/Substantia Nigra pars reticulata (SNpr) •GABA •Substance P •Dynorphin INDIRECT PATHWAY: Striatum to Globus Pallidus pars externa (GPe) •GABA •Enkephalin FEEDBACK LOOP Striatum to Substantia Nigra pars compacta (SNpc) •GABA •Substance P •(Neurotensin) •Dynorphin Principle Amino Acid Transmitters in the Mammalian Central Nervous System Excitatory Amino Acids •Glutamate (Glu) •Aspartate (ASP) These depolarize neurons in the mammalian CNS Inhibitory Amino Acids •γ-aminobutyric acid (GABA) •Glycine (Gly) •Taurine •β-alanine These hyperpolarize neurons in the mammalian CNS Classification of Ionotropic Glutamate Receptor Subtypes IONOTROPIC GLUTAMATE RECEPTOR SUBTYPE Subunits Agonists Actions AMPA gluR1 GluR2 GluR3 GluR4 Glutamate or AMPA Increase Na+ and Ca2+ influx, increase K+ efflux (N.B. receptors with GluR2 have ion channels with decreased Ca2+ permeability) Kainate GluR5 GluR6 GluR7 KA1 KA2 Glutamate or kainate Increase K+ efflux NMDA NR1 NR2A NR2B NR2C NR2D Glutamate or NMDA and glycine and membrane depolarization Increase Ca2+ influx, increase K+ efflux Metabotropic Glutamate Receptor (mGluR) Subtypes and Their Actions Group Subtype Actions I mGluR1 MGluR5 Activated adenylyl cyclase → increases cAMP (mGluR1 only) Increases PLC activity → PIP2 hydrolysis → increases IP3 and DAG → increases Ca2+ levels, stimulates PKC Inhibits K+ channels II MGluR2 mGluR3 Inhibits adenylyl cyclase → decreases cAMP Inhibits voltage-sensitive Ca2+ channels Activates K+ channels III mGluR4 mGluR6 mGluR7 mGluR8 Inhibits adenyly cyclase → decreases cAMP Inhibits voltage-sensitive Ca2+ channels Group I mGluRs activate adenylyl cyclase and phospholipase C(PLC), while group II and group III mGluRs inhibit adenylyl cyclase. The downstream effects of mGluRs on ion channels and complex and varied. Some of the main actions on ion channels are listed. Note that the actions of group I receptors are generally excitatory, while those of groups II and III receptors are generally inhibitory. Function of the Basal Ganglia • Motor Function • Gating Function • Cognitive Function • Emotion and Motivational Behavior Projection Targets Fiber Type or Neuron Deep Nuclei Purkinje Basket Climbing + + Mossy + ? Stellate Granule ? + Golgi Action Neurotransmitter ? Excit. Aspartate + Excit. Acetylcholine Cerebellar Neurons Neuron Type Layer Projection Action Neurotransmitter Purkinje Principal (projection) Purkinje Deep cerebellar nuclei Lateral vestibular nucleus Intrinsic neurons Inhib. GABA Basket Interneuron Molecular Purkinje cell Inhib. GABA Stellate Interneuron Molecular Purkinje cell Inhib. GABA Granule Interneuron Granule Purkinje cell Basket Cell Stellate Cell Golgi Cell Excit. Glutamate Golgi Interneuron Granule Granule Cell Inhib. GABA Similarities Between the Basal Ganglia and Cerebellum • Components of the Motor System • Influence cerebral cortical activity via the Thalamus • Linked with the Cerebral Cortex via recurrent loops • Have internal (local) circuitry that modulates loop activity • Receive modulating inputs that influence their activity Eg: ¾Climbing fibers in cerebellum ¾Dopamine inputs in basal ganglia