04/12/23 Pan W 1

Introduction to Neurobiology of Disease

Overview of neurological disorders Common mechanisms Animal models Integration of basic and clinical

perspectives

Approaches to neurological diseases

1. Localization in the neuraxis

Focal vs multifocal vs diffuse

CNS – cerebrum, WM, BG, thalamus, hypothalamus, cerebellum, CNI-II, BS, SC

PNS – CNIII-XII, cauda equina, roots, plexuses, peripheral nerves, NMJ

Muscle

Approaches to neurological diseases2. Categorization – nature of the lesion

Congenital or developmental Vascular Neoplastic Traumatic Systemic – toxic Degenerative Infectious Inflammatory, autoimmune, or demyelinative Epileptic Psychiatric

Approaches to neurological diseases

3. Pattern recognition through history and exams

Paroxysmal vs acute vs chronic time courseNeurological symptoms and examination make the

specialty specificTests of CSF, imaging, neuropathology,

neurophysiology (EMG & EEG), and CNS functions (fMRI, SPECT, neuropsychological testing)

Many syndromes

Neurobiological mechanisms

Development Excitability Programmed cell death Repair

Ramon y Cajal

Neuroembryology

Wilhelm His (1831 – 1904)

Santiago Ramon y Cajal (1852 – 1934)

-Synapse-Growth cone-Tropisms

-Contiguity vs continuity-Protoplasmic outgrowth vs cell chains & other models in the origin of nerve fibers

Surface ectoderm (primary epidermis)

Neural crest (peripheral nerves,pigment, facial cartilage)

Neural tube (brain and spinal cord)

Interestingly, the vascular endothelial cells forming the BBB are from the mesoderm…

TEM picture of a growth cone“neural crest cells on a leash”-The locomotor organelle of the neuron-Senses environmental cues

tubulinactin in filopodia(phalloidin staining)

Development Migration & Synaptogenesis

- cortical proliferation zones; cortical lamination; radial glia; gliogenesis and myelination; synaptic targeting

Activity-dependent plasticity in developing neural circuits-abnormal cell migration, sprouting, or connectivity neonatal seizures

Glial-neuronal interactions

Animal models - dismyelination and demyelination

Trembler mouse: defective Schwann cells Jimpy mouse: meylin deficiency in the CNS EAE: autoimmune demyelination

Animal models for epilepsy

Tottering, lethargic, ducky, stargazer, stargazer-3 Jackson, waggler

Defective voltage-dependent Ca channel Models for absence seizures

Excitability Mechanisms of excitability: membrane

receptors, intracellular events, depolarization-induced injury

Epilepsy: abnormal synchronization Ion channel diseases – channelopathies

affecting nerve, muscle, and the brain

Copyright ©1999 by the National Academy of Sciences

Cooper, Edward C. and Jan, Lily Yeh (1999) Proc. Natl. Acad. Sci. USA 96, 4759-4766

Channelopathy

Ion channel disorders affecting muscles and peripheral nerves Mutations in the pore-forming subunits of sodium

and chloride channels myotonia Mutations in muscle sodium and calcium channels

periodic paralysis Mutations in the sarcoplasmic calcium release

channel malignant hyperthermia acetylcholine receptor mutations reduce the number

of channels at the cell surface or affect rate of opening myesthenia syndromes

Ion channel disorders in the CNS Neuronal Na channel: generalized epilepsy

with febrile seizures plus M-type K channel: benign neonatal

familial convulsions K channel (likely): episodic ataxia with

myokymia

Best comprehensive review:

http://www.neuro.wustl.edu/neuromuscular/mother/chan.html

Cell death in neurobiology Programmed cell death neurodegeneration

Apoptosis

Two phases: latent & execution Genetic analysis in C. elegans: ced-3, ced-4, and

ced-9 cell death genes Proteins regulating apoptosis: Bcl-2 family; p53 Executing proteins: caspases, scaffolding

proteins, adapters, caspase activated DNase Two pathways leading to cell death: the death

receptor (Fas) & mitochondrial pathways Apoptosis is a key factor in neurodegnerative

disease

Trinucleotide repeat diseases Polyglutamine disease – CAG repeats

DRPLA (dentatorubral pallidoluysian atrophy), Huntington’s Disease, SBMA (spinal and bulbar muscular atrophy or Kennedy’s disease), SCA1,2,3,6,7

Non-polyglutamine diseaseFRAXA, FRAXE (CGG), FRDA (GAA, in intron), DM (myotonic dystrophy, CTG), SCA8, SCA12

Animal models for neurodegeneration

Alzheimer’s disease: APP transgenic Amyotrophic lateral sclerosis: SOD1-G93A; NMD

mutants (defect in Ig S-mu binding protein 2)

Ataxia: Harlequin mouse; cerebellar deficient folia (cdf) mouse

Huntington’s disease: R6/2 strain with expanded CAG repeat

Parkinson’s disease: alpha-synuclein transgenic Spinal muscular atrophy: mutation in survival

motor neuron (smn) gene

Repair Neurotrophins Gene therapy

Pan W, CPD 11:10 &11 preface

Neurobiology of obesity: Nature Neurosci. April 2005

Integration of basic neuroscience and clinical neurology

Treatment based on mechanisms Multipotency of drugs Animal models reflect certain aspects of

human disorders Think the organism as a whole

Summary

Development, remodeling, and neuroplasticity

Excitability Balance of trophic support and apoptosis Neuroendocrine circuits and rewarding

pathways Environmental factors – the BBB,

interactions between neurons and glia

What is your role as a neurobiologist?

The end