1Lecture 12NeurotoxicityPart IES/RP 531Fundamentals of Environmental ToxicologyInstructor: Allan [email protected] 2005Context: Why Study Neurotoxicity?• The pharmacodynamic action of mostinsecticides is at the level of nerve function• The ultimate biochemical receptors are atdifferent sites of the nerve cell• Some insecticides are extremely persistent inenvironment and in tissues– These are banned from commercial use butresidues still bioaccumulate in the food web• Modern insecticides are easily biodegradablein the environment and easily metabolized– But a number of commonly used insecticides havevery high acute toxicities against nontargetinvertebrates, aquatic and terrestrial vertebratesContext: Why Study Neurotoxicity• In addition to the historical issues of neurotoxicinsecticides and acute toxicity to birds and fish,concerns about neurodevelopmental toxicityhave grown– Indeed, these have been addressed for humans inthe Food Quality Protection Act of 1996, a majoramendment to the Federal Insecticide FungicideRodenticide Act (FIFRA)• Historical concerns over neurotoxicologicaleffects of lead and mercury• New concerns over potentialneurodevelopmental effects of PCBs andPBDEsNerve Physiology• Nerve function is remarkably conservedacross both invertebrates andvertebrates– Earliest knowledge of how nerves workcame from experiments using the squidgiant axon, which was several mm inthickness• Thus, toxicants that act at the level ofthe nerve can potentially have adverseeffects across a wide spectrum oforganismsIntroduction to Nervous System & Nerve Physiology• Rapid coordination in the body• Electrically excitable cells (neurons)• Generate electrical signals long distanceswithout degrading strength of signal• Function similarly among all animals• Basic structure– Soma (cell body; contains nucleus; metabolicmaintenance of cell)– Dendrites (receive & carry signal towardsoma)– Axons (carry signal away from soma)– Supporting cells (for ex., myelin sheath)Organization of Nervous System• Sensory neurons– Transmit information collected from external stimuli– Respond to stimuli inside body• For ex., blood oxygen level, position of a joint,orientation of the head• Interneurons– Link other neurons within the central nervous system• Networked to exchange information and performcomplex “computations” leading to behavior (or thought)Rabbit RetinaInterneurons2• Motor neurons (motoneurons)– Carry instructional signals to effector organs• An effector is a cell, tissue, or organ that acts tochange the condition of an organism inresponse to neuronal or hormonal signals• For ex., contraction of muscles or secretions byglandsOrganization of Nervous System• Neurons grouped into clusters in almost all phyla• Typically, the cell bodies or soma are contained withinthe central nervous system (CNS), which consists of a--– Brain (located in the anterior position or head)– Nerve cord (extends posteriorly along the body midline)• Invertebrates have collections of neuronal somata called gangliaalong the nerve cord– Control local regions of body– Insects et al. Ventral nerve cord (lies along ventral midline)• Vertebrates have ganglia, but located outside the CNS– Spinal cord = nerve cord (dorsal midline)• Soma may lie in CNS but they send out long axons toperipheral parts of body– To collect sensory information– To deliver motor signals that control the activity of muscles orglands• Supportive cells (structural, insulative, and metabolic)– Glial cellsOrganization of Nervous SystemOrganization of Nervous System--InvertebrateLeechCrayfishAbdominalgangliaBrainThoracicgangliaVentral Nerve CordNote segmented nature of nervous system prevalent in invertebrates.Adopted from Randall et al. 2002 “ Eckert’sAnimal Physiology: Mechanisms &Adaptations” 5th Ed.”Organization of Nervous System--Invertebrate Neuronal Circuit• Afferent neuron carriessensory information tointerneurons in theCNS– Afferent: transporting orconducting to a centralregion• Efferent neuron carriesprocessed informationto effector organs– Efferent: transporting orconducting to theperiphery from a centralregionCNSAdopted from Randall et al. 2002 “Eckert’s AnimalPhysiology: Mechanisms & Adaptations” 5th Ed.”Organization of Nervous System--Vertebrates Maintain Segmental StructureFrog HumanAdopted from Randall et al. 2002“Eckert’s Animal Physiology:Mechanisms & Adaptations” 5thEd.”Nerve Morphology• Neuron (single cell)– Cell body (contains nucleus)– Branching fibers• Axon• Dendrites– “Insulating” membrane or sheath called themyelin– Gap at nerve terminals called the synapse3NucleusCell BodyAxonDendriteSynapseImpulseDirectionSynapsePicture from Scientific AmericanTransmission of Nerve Signals--Overview• Plasma membrane of soma and its dendrites receive “signals” from theterminals of other neurons• The “spike-initiating zone” (usually located at junction of the soma andaxon; a.k.a. axon hillock) integrates the input signals from many neurons• Spike-initiating zone with sufficient input will initiate a change in plasmamembrane voltage potential and generate an action potential (AP)– Action potentials are what are commonly thought of as the nerveimpulse or signalIntegrationSpikeInitiationImpulse Conduction (AP)Glial CellsForming InsulatingMyelin SheathAxon terminalsSomaDendritesDirection ofsignal conductancePicture modified from Randall et al. 2002 Eckert’s Animal PhysiologySoma integrates multiple input signals from other nervesthat terminate at the dendrites and soma itselfAxon HillockAxonDendritesNucleus ofSomaNerve terminals fromother neuronsSufficientincoming signalstrigger the AP atthe axon hillockregion.The incomingsignals produce agraded response,but the AP is anall-or-nonechange inmembranepotential.Nerve Signal (Impulse) Conduction• Because of the synapse, nerve signals onlytravel one direction down the axon– Nerve signal is actually an electric current thatmoves along the axon until it reaches the synapse,which separates the axon and the dendrite• Ability to conduct electrical current is due totwo factors:– Membrane electrical potential– Permeability of the membrane to ions• A measurable electricalpotential difference existsacross cell membrane (i.e.,potential difference on outsidevs. inside of cell membrane)– Inside of cell is negativewith respect to