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Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists.

ABSTRACT: Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABA(B) receptors is significantly increased in the dentate gyrus of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABA(B) receptors in cognitive deficits in DS by defining the effect of selective GABA(B) receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABA(B) receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition, and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor, equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABA(B) receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABA(B) receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABA(B) receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS.

SUBMITTER: Kleschevnikov AM

PROVIDER: S-EPMC3411326 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To determine the precise effects of post-traumatic seizure activity on hippocampal processes, we induced seizures at various intervals after traumatic brain injury (TBI) and analyzed plasticity at CA1 Schaffer collateral synapses.Rats were initially separated into two groups; one exposed solely to fluid percussion injury (FPI) at 2 Psi and the other only receiving kainic acid (KA)-induced seizures without FPI. Electrophysiological (ePhys) studies including paired-pulse stimulation for short-term presynaptic plasticity and long-term potentiation (LTP) of CA1 Schaffer collateral synapses of the hippocampus for post-synaptic function survey were followed at post-event 1 hour, 3 and 7 days respectively. Additional rats were exposed to three seizures at weekly intervals starting 1 week or 2 weeks after TBI and compared with seizures without TBI, TBI without seizures, and uninjured animals. An additional group placed under the same control variables were treated with levetiracetam prior to seizure induction. The ePhys studies related to post-TBI induced seizures were also followed in these additional groups.Seizures affected the short- and long-term synaptic plasticity of the hippocampal CA3-CA1 pathway. FPI itself suppressed LTP and field excitatory post synaptic potentials (fEPSP) in the CA1 Schaffer collateral synapses; KA-induced seizures that followed FPI further suppressed synaptic plasticity. The impairments in both short-term presynaptic and long-term plasticity were worse in the rats in which early post-TBI seizures were induced than those in which later post-TBI seizures were induced. Finally, prophylactic infusion of levetiracetam for one week after FPI reduced the synaptic plasticity deficits in early post-TBI seizure animals.Our data indicates that synaptic plasticity (i.e., both presynaptic and postsynaptic) suppression occurs in TBI followed by a seizure and that the interval between the TBI and seizure is an important factor in the severity of the resulting deficits. Furthermore, the infusion of prophylactic levetiracetam could partially reverse the suppression of synaptic plasticity.

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Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists.

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