Narcolepsy

Question 1

Tafti 2014

Answer 1

DQB1 gene implicated by GWAS in europe

Question 2

Sakurai 1998

Answer 2

Orexin injection = satiated rats keep eating

Question 3

Orexin

Answer 3

Synthesised in lateral ht, neurons innervate areas involved in CV function, eating behaviour, sleep/wake cycles e.g. basal forebrain, HC, ht etc.
Increase arousal, locomotor activity, and BP but suppress REM

Question 4

Lecea 1998

Answer 4

Staining of O neurons: lots in lateral ht, also arcuate nuclei of mediobasal hypothalamus (stimulates food intake)

Question 5

Yamanaka 2003

Answer 5

O neurons activated by low glucose. O K/O mice don’t show normal response to fasting (usually increased arousal and locomotor activity)

Question 6

Mochizuki 2014

Answer 6

Behavioural state instability model (not due to circadian function, homeostatic dysfunction etc). Mice lacking O = low threshold to change between sleep/wake states so transition rapidly.
Lack of O signalling = sporadically-activated VLPO neurons

Question 7

OXR1 and OXR2 K/O mice

Answer 7

Also show behavioural state instability and narcolepsy-like phenotype

Question 8

Dog narcolepsy models

Answer 8

Dobermann Pinschers: autosomal recessive mutation on Hcrt2/OX2R gene so truncated receptor, can’t bind O.
Also Labradors and Dachshunds also have mutation in Hcrt2/OX2R = similar phenotype.

Question 9

Adamantadis 2007

Answer 9

Optogenetics: selectively activate cells using light.
Blue light activates O neurons = transition from SWS to awake/REM.
Orange = awake to SWS.
So O neurons directly involved in driving sleep/wake states.

Question 10

Peyron 2000

Answer 10

Human autopsy staining: no orexin mRNA in lateral ht

Question 11

Thannickal 2000

Answer 11

Sig reduced O neurons in throughout ht

Question 12

Saper and Scammell 2004

Answer 12

Modafinil: unsure of exact mechanisms. But increases NA, HA, 5HT, orexin signalling. Wake-promoting.

Question 13

Abad 2017

Answer 13

90% patients need drugs. Treat both EDS and cataplexy.
Modafinil 1st line, wake-promoting, although only treats EBS.
SSRIs and SNRIs for cataplexy: because O neurons linked to monoamine cells groups e.g. raphe nuclei (5HT), LC (NA) which can modulate N symptoms. But how?
Sodium oxybate first line for both EDS and cataplexy.
Emerging treatments = immunotherapy to stop destruction of O cells, orexin replacement therapy (intracerebral injection of orexin).
Also behavioural e.g. good sleep hygiene, scheduled naps.