Copyright 2008, The Johns Hopkins University and Tomás Guilarte. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided “AS IS”; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License . Your use of this material constitutes acceptance of that license and the conditions of use of materials on this site.
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Copyright 2008, The Johns Hopkins University and Tomás Guilarte. All rights reserved. Use of these materials permitted only in accordance with license rights granted. Materials provided “AS IS”; no representations or warranties provided. User assumes all responsibility for use, and all liability related thereto, and must independently review all materials for accuracy and efficacy. May contain materials owned by others. User is responsible for obtaining permissions for use from third parties as needed.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License. Your use of this material constitutes acceptance of that license and the conditions of use of materials on this site.
The scientific study of chemical agents that cause adverse structural or functional effects on the nervous system
5
Nervous System
Central nervous system (CNS)−
Brain
−
Spinal cordPeripheral nervous system (PNS)−
Sensory nervous system
−
Motor nervous system−
Autonomic nervous system
6
Major Subdivisions of the CNS
Forebrain−
Telencephalon: cerebrum
−
Diencephalon: thalamus, hypothalamusMidbrain−
Substantia nigra
Hindbrain−
Pons/medulla oblangata
−
Cerebellum
7
Blood-Brain Barrier
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Blood-Brain Barrier
Endothelial cells that line capillaries in brain and peripheral nervesThey form tight junctions and restrict the entry of substances into the brain
9
Nervous System Cell Types
Neurons −
Basic functional unit of the nervous system
−
Receive, integrate, and transmit information
10
Nervous System Cell Types
Glial cells −
Supporting cells with metabolic, structural and immunologic function
−
In CNSOligodendrocytes (myelin)Astrocytes (metabolic function)Microglia (immunological function)
−
In PNS: schwann cells
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Neuron: A Nerve Cell
12
A
B
C
D
E
Propagation of Action Potential
13
Subcellular Components
14
Chemical Neurotransmission
Neurotransmitters are stored in vesicles in the nerve terminalsThe presynaptic membrane is depolarized and calcium enters the presynaptic terminal via voltage-sensitive calcium channelsVia a complex process, vesicles fuse with the presynaptic membrane and release contentsNeurotransmitter released into the synaptic cleft binds to a specific receptor in the postsynaptic membranes and produces an effect on the receiving cell (postsynaptic)
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Synapse
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Chemical Neurotransmission Illustration
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Mechanisms for Terminating Neurotransmission
1.
Enzymatic degradation of neurotransmitter−
Example: acetylcholine/AChE
2.
Active transport of neurotransmitter−
Presynaptic terminal high affinity transporters
Example: dopamine and serotonin−
Glial cells uptake surrounding synapse
Example: glutamate3.
Diffusion away from the synapse (general)
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Neurotransmitters: Major Classes
1.
Acetylcholine
2.
Biogenic amines−
Dopamine
− Serotonin
− Norepinephrine
− Epinephrine
3.
Amino acids−
Excitatory: glutamate, aspartate
− Inhibitory: GABA, glycine
4.
Neuropeptides−
Many different types—e.g., opioids, somatostatin
Section B
Factors that Mediate Brain Injury by Environmental Agents
20
Vulnerability of CNS to Injury
Inherent susceptibility of early neurological processes such as cell migration, differentiation, and synaptogenesisHigh metabolic demand in order to maintain ionic gradients−
Deprivation of oxygen even for short times could be lethal to neurons
Lipid-rich environment Shape of neurons and axonal extensions−
Proteins and other organelles are synthesized in cell bodies and transported to nerve terminals and other compartments
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Why Is Neurotoxic Injury Critical?
Repair mechanisms are limited Neurotoxic injury may amplify neurological consequences of disease and/or agingNeurotoxic injury may result in multiple outcomes such as:−
Sensory disorders
−
Movement disorders−
Learning disorders
−
Memory disorders
22
Patterns of Neurotoxic Injury
Neuronopathy: total neuronal lossAxonopathy: retrograde axonal lossMyelinopathy: loss of myelin contentTransmission toxicity: interference with synaptic components
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Sources of Neurotoxicants
1.
Naturally occurring in edible plants and animals
2.
Anthropogenic sources
3.
Endogenous
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1. Naturally Occurring in Edible Plants and Animals
Tetrodotoxin−
Puffer fish
−
Blocks ion channelsDomoic acid−
Shellfish
−
Excitatory amino acid receptor agonist−
Causes seizures and cell death in limbic regions (hippocampus)
BMAA (B-N-methylamino-L-alanine)−
Excitatory amino acid receptor agonist
−
Present in cycad seed−
Believed to be associated with Guam Amyotrophic Lateral Sclerosis-Parkinsonism dementia
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2. Anthropogenic Sources
Heavy metals: lead, manganese, cadmiumSolvents: carbon disulfide, n-hexane, etc.Pesticides, fungicides, and insecticides: chlorpyrifos, rotenone, organophos-phates, carbamates, etc.Drugs of abuse: cocaine, methamphet-amine, LSD, MDMA (ecstasy)
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3. Endogenous
Metabolic abnormalities: can lead to an increase in endogenous substances that may cause damage to the CNS−
For example: concentrations of the naturally-occurring excitatory amino acid glutamate can increase dramatically following hypoxia, hypoglycemia, and stroke—and produce excitotoxic cell death
−
Tryptophan metabolites, such quinolinic acid and 3-
hydroxykynurenine, have been demonstrated to produce cell death and may be linked to some neurodegenerative conditions
Section C
MPTP and Parkinson’s Disease
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Case Study 1
Case Study 1: Environmental Toxicants as Sources of Parkinson’s DiseaseCase study MPTP−
[1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]
Other potential toxicants associated with a Parkinsonian syndrome−
Manganese
−
Pesticides and insecticides—e.g., rotenone−
Drugs of abuse—methamphetamine (?)
29
Parkinson’s Disease: Characteristics
Parkinson’s disease (PD) is a neurodegenerative disorder of the basal gangliaThe onset of disease is usually in the fifth or sixth decade of life, although cases at earlier ages have been reportedEtiology of PD is unknown−
Substantial experimental evidence suggests that environmental factors play an important role
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Parkinson’s Disease: Characteristics
PD patients express:−
Tremor at rest
−
Increased muscle tone or rigidity−
Slowness in the initiation of movement (akinesia)
−
Slowness in the execution of movement (bradykinesia)
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Neuropathology of Parkinson’s Disease
Degeneration of dopaminergic neurons in the substantia nigra that innervate basal ganglia (caudate/putamen) structures Decreased concentrations of dopamine in the caudate/putamen
32
Neuropathology of Parkinson’s Disease
Decreased levels of other markers of neuronal integrity, including:−
Tyrosine hydroxylase (TH)
−
Dopa decarboxylase (DDC)−
Dopamine transporter (DAT)
−
Vesicular monoamine transporter-type 2 (VMAT-2)
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Dopaminergic System: Rat Brain
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Unsuspected Synthesis of MPTP
35
Metabolic Activation of MPTP
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MPP+ Inhibits Energy Production
37
Comparison of the Major Clinical Signs of the NMPTP-Induced Neurological Disorder in Man and the Monkey
There is clear experimental evidence that some neurodegenerative disorders have an environmental etiology; Parkinson’s disease appears to be a consequence of gene-environment interactionChronic or acute exposures to certain environmental toxicants may interact with specific gene products to cause the demise of dopaminergic neurons
Section D
Lead Neurotoxicity
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Case Study 2
Case Study 2: Childhood Lead Intoxication Effects on Learning and Memory Function
42
Lead: An Historical Perspective
Lead (Pb) is the oldest, most extensively studied, and probably the most ubiquitous neurotoxic substance known to manPb is mentioned in ancient Egyptian manuscripts and was used as a cosmeticThe Romans used it in cooking tools and vesselsThe Romans used it as a sweetener and preservative in wines and cidersLead acetate is often called “sugar of lead” because of its sweet tasteThe Romans used it in building homes and transporting waterThe word plumber originates from the Latin word for Pb, plumbum
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Lead: An Historical Perspective
Pb toxic effects have been recognized for centuries−
Ancient writings form the Greek thinker Dioscorides in the 2nd century B.C. states “Lead makes the mind give way”
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Lead: An Historical Perspective
Benjamin Franklin recognized Pb as an occupational hazard−
In a letter he wrote about Pb poisoning: “How long a useful truth may be known and exist, before it is generally received and practiced on”
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Childhood Lead Exposure: A Global Problem
Lead intoxication poses one of the greatest environmental threats to children in America (Satcher, U.S. Surgeon General, 2000)In the United States, one in twenty children has blood lead >10 μg/dL38 million housing units in the United States have lead-based paint, and 24 million have significant lead-based paint hazards (Jacobs et al., Env. Hlth. Persp. 110: A599, 2002)
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Childhood Lead Exposure: A Global Problem
Emerging data indicates that a greater number of children are being exposed to greater levels of lead in developing and industrialized nations (e.g., Latin America, Russia, and China)In China alone, current sampling indicates that 65% of children tested have blood lead levels >10 μg/dL (Env. Hlth. Persp. 110: A567, 2002)Latest research findings indicate that lifetime blood lead exposure < 5 μg/dL produces learning deficits greater than at higher exposures
Notes Available
47
Lead Toxicity in Children
Blood lead and measures of intelligence (IQ, math, reading) inversely related (Bellinger, 1996)Multi-center study of children exposed to Pb shows that succimer chelation therapy, the primary means of treating Pb-poisoned children, had no significant impact on cognitive deficits (Rogan et al., 2001)Latest studies suggest a connection between childhood lead intoxication and delinquent behavior
Notes Available
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Experimental Paradigm
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Blood Levels as a Function of Dose
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Brain Lead Levels as a Function of Dose
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Spatial Learning Task
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Rat on Submerged Platform
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Rat Being Placed in Water in One Quadrant of Pool
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Rat Swimming
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Rat Guided to Platform
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Day
1
Day 9
Control 1500
PbAc
Tracking of Swimming Path
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Acquisition of Learning Behavior
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Schematic of NMDA Receptor Complex
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Control 1500 ppm PbAc
NR1-
pan
NR2A
Nihei et al., Neuroscience 99:233, 2000
CA
DG
GluR1
In Situ Hybridization
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Levels of Gene Expression
61
Case Study 2: Summary
Deficits in cognitive function are the undisputed effects of childhood Pb intoxicationThese deficits are mediated by Pb-induced alterations in the expression of genes that are essential for learning and memory function−
For example, the genes that encode for the NMDA receptor
Section D
Effect of Lead Exposure at the Cellular Level: Neurogenesis
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Neurogenic Zones in the Mammalian Brain
Source: (2007). Cell Tissue Res. 329: 409–420.
64Source: Christie and Cameron. (2006). Hippocampus.
Labeling of Progenitor Cells in the SGZ
JHSPH OpenCourseWare was unable to secure permission to display this image.
Christie BR, Cameron HA: Neurogenesis in the adult hippocampus. Hippocampus 2006;16:199-207.
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Progression of Adult Neurogenesis in the Hippocampus
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Lead and Neurogenesis: Experimental Design
Gestation Lactation
Postnatal day1 21 45 50
BrdU
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Proliferation Survival
Pb 2+
67
a
SPB
IPB
b
0.1mm
Proliferation of Newly Born Cells in the Dentate Gyrus
Chronic lead exposure in early life alters granule cell neurogenesis and morphology in the hippocampus of young adult ratsThese effects are likely to alter neuronal circuitry in the hippocampus with detrimental effects on synaptic plasticity and learning
Section E
Environment Enrichment
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Environmental Enrichment
Definition: combination of complex inanimate objects and social stimulation
JHSPH OpenCourseWare was unable to secure permission to display this image.
Guilarte T, et al: Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Ann Neurol 2003;53:50-6
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*
lead exposure enrichment
birthconception weaning
PN 1 PN 50
gestation lactation
PN 21
Water Maze
Studies*
Pb2+ Exposure, Environmental Enrichment Paradigm
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Searching Pattern on First
Trial Day
81
Acquisition of Spatial
Learning Task
82
Summary
Environmental enrichment, a way to stimulate brain function, is able to reverse the learning deficits resulting from developmental lead exposureThis approach was effective even after the lead exposure had already occurredThus, environmental enrichment may be a useful strategy for enhancing the learning capacity of children exposed to lead
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Citations
Guilarte TR, Toscano CD, McGlothan JL, Weaver SA (2003). Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Annals of Neurology, 53: 50–56.Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR (2000). N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience 99: 233–242.
