BMSN3102

Synaptic Dysfunction and Depression

Dr. L. W. LIM
School of Biomedical Sciences
The University of Hong Kong
limlw@hku.hk
 Learning Objectives

Describe the structural function of a single synapse.

Describe the pathophysiology of synaptic neurotransmission.
Describe the molecular basis of synaptic dysfunction in depression.
Neuron
Glial Cells
Do not initiate or conduct nerve impulses.
Physically, metabolically, and functionally support neurons.
4 major types: 1. Astrocytes 2. Oligodendrocytes
3. Microglia 4. Ependymal cells
Membrane Potential

+20
+10
Membrane potential (mV)

Depolarization (decrease in potential;

0 membrane less negative)
10
Repolarization (return to resting potential
20
after depolarization)
30
40 Hyperpolarization (increase in
50 potential; membrane more negative)
60
70 Resting potential
80
90

Time (msec)
Graded Potentials (act as short-distance signals)
(a) Entire membrane at resting potential

Closed channels Extracellular fluid

Unbalanced charges
distributed across
the plasma
membrane that
Portion of Intracellular fluid are responsible for
an excitable membrane potential
cell

(b) Inward movement of Na+ depolarizes membrane, producing a graded potential

Inactive area Active area depolarized Inactive area

at resting potential (a graded potential) at resting potential

Triggering event opens ion channels, most commonly permitting net Na+ entry
Graded Potentials

(c) Depolarization spreads by local current flow to adjacent

inactive areas, away from point of origin
Current flows between the active and adjacent inactive areas

Inactive Previously Original Previously Inactive

area inactive area active area inactive area area
being depolarized being depolarized
Spread of depolarization
Action Potentials 4

Na+ channel closes and is inactivated

(activation gate still open; inactivation K+ channel opens
gate closes) (activation gate opens)

Na+ channel
reset to closed
but capable
of opening K+ channel
Na+ channel closes
opens and (activation
gate closes; (activation
is activated gate closes)
(activation inactivation
gate opens; gate opens)
inactivation
gate already
open)
3 5

K+ voltage-gated channel closed

(activation gate closed) 2
Threshold potential

1 6 8
Resting potential
7
Depolarizing
triggering event

Na+ voltage-gated channel closed

(activation gate closed; inactivation gate open)
Refractory periods
Myelin
Synapse
Synapses (the junction between neurons):
Electrical synapses: neurons connected directly by gap junctions
Chemical synapses: chemical messenger is transmitted across the junction
separating neurons (which are most common).

1
Axon of
presynaptic
neuron

Synaptic knob
Voltage-gated 2+ (presynaptic 3
Ca2+ channel Ca axon terminal)
2 Synaptic
vesicle
Neuro-
transmitter
molecule 3 Synaptic
cleft
Subsynaptic 4
membrane
5
4
Chemically gated
receptor-channel
for Na+, K+, or Cl Postsynaptic neuron
Receptor for 5
neurotransmitter
Synapse

Axon terminal
of presynaptic
neuron

Dendrite of
postsynaptic
neuron

Synaptic Synaptic
vesicles cleft
Classification of Neurotransmitters (Biochemistry)
A. Small molecules neurotransmitters (acts rapidly & acute response)
Class I : Acetylcholine (ACh)
Class II: Biogenic amines
(i) Catecholamines: Epinephrine, norepinephrine, dopamine
(ii) Serotonin
(iii) Histamine
Class III: Amino acid neurotransmitters
(i) Gamma-aminobutyric acid (GABA)
(ii) Glycine
(iii) Glutamate
(iv) Aspartate
Class IV: Nitrous oxide

B. Neuropeptide transmitters (acts slowly & prolonged effect)

Neuroactive peptides (TRH, LH, Somatostatin)
Pituitary peptides (Vasopressin, oxytocin)
Peptides acting on the gut and brain (Leucine, Enkephalin, Methionine, CCK, VIP,
Substance P, Neurotensin, Insulin)
Neuropeptides from other tissues (Angiotensin II, Bradykinin, Bombesin, Neuropeptide-)
Classification of Neurotransmitters (Physiology)
A. Excitatory
E.g. Acetlycholine, Aspartate, Dopamine, Histamine,
Norepinephrine, Epinephrine, Glumatame, Serotonin.

B. Inhibitory
E.g. GABA, Glycine

Excitation
on 5-HT
neuronal
firing

Inhibition
on 5-HT
neuronal
firing
Types of Neurotransmitters
Neurotransmitters Derivatives Synthesis Site Functions Examples of diseases
CNS, Parasympathetic Muscle action, learning
Acetylcholine Choline Alzheimers disease.
nervers and memory.
CNS, chromaffin cells Mood, hunger, sleep & Mood and anxiety
Serotonin Tryptophan
of the gut, enteric cells arousal. disorders.
Seizure, tremors, and
GABA Glutamate CNS Inhibitory function.
insomnia.
Sleep, memory, arousal,
Histamine Histidine Hypothalamus Insomnia, dementia.
hormonal secretion.
Adrenal medulla, some Emotion, Fight-or-Flight
Epinephrine Tyrosine Anxiety, phobia.
CNS cells response.
CNS, Sympathetic Emotion, alertness and Mood and anxiety
Norepinephrine Tyrosine
nerves arousal. disorders.
Movement, learning and Addiction, schizophrenia,
Dopamine Tyrosine CNS memory, attention, mood & anxiety disorders,
reward & emotion. Parkinsons disease.
Stroke, Parkinsons
CNS, gastrointestinal Emotion, learning and
Nitric Oxide Arginine disease, multiple sclerosis,
tract memory.
Alzheimer's disease.
Glutamate Glutamine CNS, spinal cord Memory, Pain. Dementia, schizophrenia.

The above description is not complete, but it provides an overall idea of the function of neurotransmitters.
Functions: Functions:
- Reward (motivation) - Mood
- Pleasure, euphoria - Memory processing
- Motor function (fine tuning) - Sleep
- Compulsion - Cognition
- Perseveration

Dopa Decarboxylase

Catechol-O-Methyltransferase
 Acetlycholine Pathway

Histamine Pathway
Glutamatergic pathway
GABA-ergic pathway
Ventral Tegmental Area Dopamine
Substantia Nigra Dopamine
Raphe Nucleus Serotonin
Locus Coeruleus Norepinephrine
Basal Forebrain - Acetylcholine
Major Depression
Anxiety, Mood Appetite

Anhedonia Motivation

Insomnia/
Worthlessness
hypersomnia

Fatigue Suicidal thought

60% of patients inadequate response to these therapies

American Psychiatric Association, 2000
 17% 3%

10%

8-12%

3-5% 8-10%

Age standardized disability-adjusted life year (DALY) rates per 100,000 inhabitants.

Kessler et al., 2005 Arch. Gen. Psychiatry

5-HT
Dorsal Raphe Courtesy from Dr LW Lim.
5-HT Neurotransmission
Antidepressant (SSRIs)
A. Selective Serotonin Reuptake Inhibitors
Clomipramine, Fluoxetine, Paroxetine, Sertraline, Citalopram
B. Indication
Depression, OCD, Panic, Bulimia, PTSD
C. Side effects
GI (nausea, vomiting, constipation),
Sexual dysfuntion (ejaculatory delay)
Antidepressant (Ketamine)
Ketamine normalizes the depressive-like behaviour
and dendritic spine in stress animal model
VIDEO: Exploring Neurotransmission