Reactive astrocytes augment hippocampal inhibitory tone via GABA
transporter-3/4 to facilitate synaptic balance in Alzheimer’s disease
Abstract
Background and Purpose: Cognitive decline is a major symptom in
Alzheimer’s disease (AD), which is closely associated with synaptic
excitatory-inhibitory imbalance. Here, we investigated whether
astrocytic mechanisms involving the astrocyte-specific GABA transporter
3/4 (GAT3/4) play a role in altering the synaptic balance in AD and
whether these mechanisms correlate with presynaptic cannabinoid type-1
receptors (CB1-Rs). Experimental approach: Using the APPNL-F/NL-F
knock-in mouse model of AD, aged-matched to wild-type mice, we performed
in vitro electrophysiological whole-cell recordings combined with
immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the
hippocampus. Comparative neuroanatomy experiments were also performed in
post-mortem brain tissue from human AD patients, age-matched to healthy
controls. Results: We observed a higher expression of GABA content and
GAT3/4 co-localised with reactive astrocytes, which enhanced tonic
inhibition in the CA1, and DG of APPNL-F/NL-F mice compared to the
age-matched wild-type animals. Blocking GAT3/4 - associated tonic
inhibition in APPNL-F/NL-F mice resulted in an enhanced frequency of
synaptic excitation, suggesting a presynaptic mechanism. These data also
correlated with an up-regulation of CB1-Rs in astrocytes and
cholecystokinin (CCK)-containing interneurons, which also enhanced tonic
inhibition in the AD model, but did not affect GAT3/4 -associated tonic
inhibition. The neuroanatomical results were mirrored in post-mortem
tissue of AD patients. Conclusions: Our data suggest that reactive
astrocytes lead to augmented tonic inhibition in the hippocampus, which
probably plays an important presynaptic compensatory role in attempting
to restore AD-associated neuronal hyperactivity. Therefore, reducing
tonic inhibition through GAT3/4 may not be a good therapeutic strategy
for AD.