Lecture 34 - Pathophysiology of CNS Disorders

Question 1

Hindbrain consists of

Answer 1

medulla, pons, cerebellum

Question 2

Midbrain consists of

Answer 2

substantia nigra

Question 3

Forebrain consists of

Answer 3

cerebral cortex
basal ganglia: striatum (caudate and putamen), globus pallidus, subthalamic nucleus
limbic system: hippocampus, amygdala diencephalon: thalamus, hypothalamus

Question 4

Medulla

Answer 4

autonomic functions - control of involuntary functions
includes centers for controlling respiration, cardiac function,
vasomotor responses, reflexes (e.g. coughing)

Question 5

Pons

Answer 5

“bridge” to cerebellum and forebrain
relays signals from the forebrain to the cerebellum

Question 6

Cerebellum

Answer 6

“little brain”
governs motor coordination for producing smooth movements undergoes neurodegeneration in spinocerebellar ataxias (uncontrolled disjointed/jerky movement)

Question 7

Substantia nigra

Answer 7

consists of 2 sub-structures
SN pars compacta
=> provides input to the basal ganglia, supplies
dopamine to the striatum
=> involved in voluntary motor control
(‘movement with intention’) and some
cognitive functions (e.g. spatial learning)
=> undergoes neurodegeneration in PD
SN pars reticulata has an output function, relays signals from the basal ganglia to the thalamus

Question 8

Forebrain

Answer 8

• cortex (cerebrum)
  → involved in processing and interpreting information
• basal ganglia: striatum (caudate & putamen), globus pallidus, subthalamic nucleus
  → voluntary motor control, some cognitive functions
• limbic system
  → emotions (amygdala), memory (hippocampus)
• diencephalon:
  → thalamus: ‘relay station’ to and from the cortex (voluntary motor function)
  → hypothalamus:
  => regulates internal homeostasis, emotions
  => hormonal control (through the pituitary
  gland) and direct neural regulation (involuntary motor function)

Question 9

The cortex is involved in

Answer 9

decision making, higher level functions
- our senses receive information about the environment, which is passed through the thalamus, to the cortex, and back.
- ‘decisions’ are made in these cortico-thalamic loops about how to interpret and act on the incoming sensory information.
- damage to the cortex can affect movement, speech, personality.
- schizophrenia is considered a disease of the frontal cortex

Question 10

Which of the following brain structures is directly involved in controlling involuntary functions?

Answer 10

hypothalamus
medulla oblongata

Question 11

The CNS consists of

Answer 11

neurons and glial cells

Question 12

Glial cells

Answer 12

astrocytes
oligodendrocytes
microglia

Question 13

Astrocytes

Answer 13

• provide neurons with growth
  factors, antioxidants
• remove excess glutamate
  (excitotoxic neurotransmitter)
• support the blood-brain barrier

Question 14

Oligodendrocytes

Answer 14

• produce myelin sheath that
  insulates axons

Question 15

Microglia

Answer 15

• provide growth factors
• clear debris (e.g. myelin debris)
  by phagocytosis
• role in neuroinflammation (in CNS diseases, microglia are overactive and can harm others)

Question 16

Blood-brain-barrier is stabilized by

Answer 16

tight junctions in the endothelial cell layer of blood vessels in the brain.
drugs have to be small enough or hydrophobic enough to get through the BBB

Question 17

Neurotransmission involves

Answer 17

a release of synaptic vesicles from boutons into the synaptic gap (cleft).

Question 18

Neurtransmission is triggered by

Answer 18

electrical depolarization of the neuron (influx of Na+ ions that changes the charge polarity of the membrane).

Question 19

Action potentials last

Answer 19

0.2-0.5 msec
action potentials for a single neuron are always of the same magnitude (‘all or none’)

Question 20

Refractory period

Answer 20

period after action potential (hyperpolarized phase) during which a neuron will not fire again.

Question 21

Current carried by a nerve fiber (bundle of axons) is

Answer 21

greater as a result of summation

Question 22

Excitatory neurotransmitters induce EPSPs

Answer 22

• definition of EPSP: excitatory postsynaptic potential
  (subthreshold depolarization peak)
• excitatory neurotransmitter acts on an ionotropic receptor,
  allowing Na+ ions to cross the membrane.
• an increase in the strength of the stimulus will increase the magnitude of the depolarization, so that the threshold depolarization to trigger an action potential is achieved.

Question 23

Inhibitory neurotransmitters induce IPSPs

Answer 23

• definition of IPSP: inhibitory postsynaptic potential
• inhibitory neurotransmitter induces hyperpolarization by allowing Cl- ions to cross the membrane.
• an IPSP can decrease the magnitude of a subsequent EPSP.

Question 24

How do drugs act in the CNS? What are the mechanisms?

Answer 24

• generally drugs act in the CNS by modulating synaptic neuro- transmission:
  → some drugs act as agonists, antagonists, or partial agonists at synaptic receptors
  → other drugs target mechanisms involved in metabolizing (or removing) transmitter from the synaptic cleft.
  => enzymatic metabolism
  => transport into the presynaptic neuron or a neighboring glial cell
  → in many cases the underlying molecular mechanisms aren’t clear – but we do know about effects on neurotransmission.

Question 25

Common amino acid (aa) neurotransmitters

Answer 25

(1) GABA (gamma aminobutyric acid)
(2) glycine
(3) glutamate

Question 26

GABA (gamma aminobutyric acid)

Answer 26

throughout the brain
- major inhibitory neurotransmitter in the brain. (hyperpolarization)
- depresses neuronal excitability by increasing the flux
of Cl- ions into the neuron.
- there are GABA-A and GABA-B receptors.
- drugs that interact with GABA pathways are generally
CNS depressants and include:
*Sedative hypnotics (benzodiazepines, barbiturates)
*Anticonvulsants
*Anxiolytics
glycine is similar to GABA but acts in the spinal cord

Question 27

GABA receptor

Answer 27

GABA(A) - ion channel
GABA(B,C) - GPCR

Question 28

Glutamate

Answer 28

throughout the brain
- major excitatory aa neurotransmitter in the brain. (depolarizes)
- excess glutamate can cause neuronal damage by allowing excessive Ca2+ influx into the neuron.
- glutamate receptors are metabotropic (GPCRs - metabolic rxns involving phosphorylation) or ionotropic (NMDA and AMPA - receptors that bind glutamate that are activated by glutamate and allow for influx of ions).

Question 29

Glutamate receptor

Answer 29

AMPA, NMDA - ion channel
mGluR - GPCR

Question 30

Common non-amino acid neurotransmitters

Answer 30

(1) acetylcholine
(2) dopamine (DA)
(3) norepinephrine
(4) serotonin; 5-hydroxytryptamine (5-HT)

Question 31

Acetylcholine

Answer 31

basal forebrain, pons, cortex, basal ganglia
- both muscarinic (M1-M5) and nicotinic
receptors (as in the periphery)
- examples of drugs targeting this form of neurotransmission are cholinesterase inhibitors (e.g. Aricept, used to treat Alzheimer’s disease).

Question 32

ACh receptor

Answer 32

nicotinic - nAChR
muscarinic - mAChR

Question 33

Dopamine

Answer 33

midbrain
- drug targets include the D1-D5 receptors (GPCRs)
and the dopamine transporter (DAT)
- DA neurons arise from the ventral tegmental area
(VTA) and the SN.
- drugs that block DAT and thus increase extracellular DA (e.g. amphetamine or cocaine) can produce euphoria and lead to addiction.
- excessive dopaminergic signaling may be involved in schizophrenia.
- loss of DA neurons in the SN is responsible for PD.
- drugs that interact with DA pathways include:
*Antipsychotics (D2 receptor antagonists)
*D2/D3 and D1 receptor agonists for PD

Question 34

Dopamine receptors

Answer 34

D1-like - Gs coupled (increase cAMP)
D2-like Gi coupled (decrease cAMP)

Question 35

Norepinephrine

Answer 35

• drug targets include the α- and β-adrenergic receptors (GPCRs) and the norepinephrine transporter (NET)
• NE axons arise from the locus coeruleus in the pons region.
• NET inhibitors are used to treat depression.

Question 36

Norepinephrine adrenergic receptor

Answer 36

alpha1, alpha2 - GPCR

Question 37

Serotonin; 5-hydroxytryptamine (5-HT)

Answer 37

midbrain/pons
- drug targets are serotonin receptors (14 GPCRs and one gated ion channel) and the serotonin transporter (SERT).
- 5-HT axons arise from a group of cell bodies called the raphe (rah-fay) nuclei.
- serotonin systems are involved in sleep, vigilance, mood, and sexual function.
- drugs that interact with 5-HT receptors include: (prevent excessive serotonin)
*5-HT2A antagonists as atypical antipsychotics
*5-HT1D agonists for migraine
*SERT uptake inhibitors for depression *5-HT2A agonists are hallucinogenic (e.g. LSD)

Question 38

5-HT receptor

Answer 38

5-HT3 - ion channel
5-HT1,2 - GPCR