"Investigation on the role of Cl- homeostasis and GABAergic transmission in sleep disorders of Down syndrome and in Prader Willi syndrome: a possible contributor to cognitive impairment"
Creators: name: BOLLA, MARIA
Publisher: name: Universit� degli studi di Genova
Year: 2020

description: GABA is the main inhibitory neurotransmitter of the central nervous system (CNS). Recently, 
GABAergic transmission has been reported to be depolarizing and possibly excitatory rather than 
inhibitory in a number of neurodevelopmental disorders both in patients and mouse models. 
In particular, the Ts65Dn mouse model of Down syndrome (DS) exhibits depolarizing GABA due to 
upregulation of the Cl- importer NKCC1 both in the hippocampus and in the cortex. Moreover, 
NKCC1 inhibition by the FDA-approved diuretic bumetanide is able to rescue inhibitory GABAergic 
transmission, synaptic plasticity and cognitive functions in Ts65Dn mice. 
Beside cognitive impairment, DS mice and people with DS show sleep disturbaces. Since sleep 
pattern is regulated by GABAergc transmission, we reasoned that the alteration of GABAergic 
transmission due to upregulation of NKCC1 might be underlying at least some of the sleep 
disturbances in DS mice. So, we characterized sleep in Ts65Dn mice and investigated the effects of 
a chronic treatment with bumetanide. We found that bumetanide ameliorates the quality of sleep 
in NREM and REM sleep phases before and after sleep deprivation and decreases abnormal 
wakefulness during light phase at baseline in Ts65Dn mice. Moreover, we also found abnormalities 
in other parameters, which could contribute to sleep abnormalities of Ts65Dn mice: an increase of 
food intake and activity (partially rescued by bumetanide) with a reduction of body temperature 
during dark phase. 
Because of the association of altered GABAergic signaling by dysregulation of the expression of 
NKCC1 (but also of the Cl- exporter KCC2) in many neurodevelopmental disorders characterized by 
cognitive or social impairment, and sleep disorders, we extended our studies to Prader Willi 
syndrome (PWS). PWS is a neurodevelopmental disorder, caused by defects of genomic imprinting 
and characterized by cognitive, social and sleep abnormalities. Here, we observed that the Snord116 
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mutant mouse model of PWS, PWScrm+/p? show an increased expression of NKCC1, specifically in the 
hippocampus in comparison to their wild-type mice. Moreover, we report that PWS mice have 
altered cognition and the circadian period in free-running conditions. In particular, mutant mice 
present defects of long-term memory and a reduced shortening of their circadian period together 
with an increase of alpha activity in dark-dark (DD). Moreover, they also show alteration of pain 
sensitivity, that could be linked to defects in the thermoregulation. Interestingly, in constrast with 
PWS people, Snord116 mutant mice showed no alterations of anxiety, repetivive, obsessive and 
social behaviors. 
In an effort to rescue cognition and the circadian phenotype by rescuing NKCC1 inhibition, we 
treated Snord116 mutant mice with bumetanide. Remarkably, bumetanide treatment resulted in a 
complete rescue of the cognitive defects and circadian alteration in DD, with no effects in controls. 
Our results suggest an important link between GABA transmission and the regulation of cognition 
and the circadian clock in PWS. In addition, the current study extends the repertoire of disorders in 
which NKCC1 inhibition attenuates behavioural deficits and proposes a new potential mechanism 
for the investigation of PWS.