Abstract: Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be responsible
for cognitive deficits observed throughout their lives. A change in the excitatory/inhibitory balance
in adulthood would alter synaptic plasticity, potentially triggering learning and memory deficits. -
Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system
and binds to GABAA receptors, opens a chloride channel, and reduces neuronal excitability. In this review
we discuss methods to alleviate neuronal inhibition in a mouse model of Down syndrome, the Ts65Dn
mouse, using either an antagonist (pentylenetetrazol) or two different inverse agonists selective for the
5-subunit containing receptor. Both inverse agonists, which reduce inhibitory GABAergic transmission,
could rescue learning and memory deficits in Ts65Dn mice. We also discuss safety issues since modulation
of the excitatory-inhibitory balance to improve cognition without inducing seizures remains particularly
difficult when using GABA antagonists.