Abstract
The hippocampus plays a critical role in learning and memory. Its correct performance relies on excitatory/inhibitory synaptic transmission balance. In early stages of Alzheimer’s disease (AD), neuronal hyperexcitability leads to network dysfunction observed in cortical regions such as the hippocampus. G-protein-gated potassium (GirK) channels induce neurons to hyperpolarize, contribute to the resting membrane potential and could compensate any excesses of excitation. Here, we have studied the relationship between GirK channels and hippocampal function in a mouse model of early AD pathology. Intracerebroventricular injections of amyloid-β (Aβ1-42) peptide—which have a causal role in AD pathogenesis—were performed to evaluate CA3–CA1 hippocampal synapse functionality in behaving mice. Aβ increased the excitability of the CA3–CA1 synapse, impaired long-term potentiation (LTP) and hippocampal oscillatory activity, and induced deficits in novel object recognition (NOR) tests. Injection of ML297 alone, a selective GirK activator, was also translated in LTP and NOR deficits. However, increasing GirK activity rescued all hippocampal deficits induced by Aβ due to the restoration of excitability values in the CA3–CA1 synapse. Our results show a synaptic mechanism, through GirK channel modulation, for the prevention of the hyperexcitability that causally contributes to synaptic, network, and cognitive deficits found in early AD pathogenesis.
Highlights
The hippocampus plays a critical role in learning and memory
To ascertain whether activation of GirK channels prevents the potential impairments produced by Aβ, we analyzed the functional capabilities of the CA3–CA1 synapse in alert behaving mice[26] by generating input/output (I/O) curves and testing facilitation evoked by the presentation of a pair of pulses to Schaffer collaterals (Fig. 2)
As hippocampal network activity is known to be altered in transgenic[4,5] and acute[30] Alzheimer’s disease (AD) models, we examined in our model the role of GirK channels in the oscillatory network activities of hippocampal circuits recorded in behaving mice with chronically implanted electrodes
Summary
The hippocampus plays a critical role in learning and memory. Its correct performance relies on excitatory/inhibitory synaptic transmission balance. GirK channel dysfunction has been linked to pathological states related with impairments in the excitatory/inhibitory neuronal activity balance such as epilepsy[16] and Down syndrome[17], both widely related with AD18. It has been described in vitro an unrecognized aberrant function of the GirK channel in AD-related synaptic pathophysiology[18,19,20] leading to increased neuronal excitability. We found that increasing GirK activity restores hippocampal synaptic plasticity and network activity, and overcomes memory deficits induced by Aβ, supporting the contention that manipulations focused on the re-establishment of network excitation/inhibition balance by preventing network hyperexcitability would provide new therapeutic approaches in the pathogenesis of AD5,18,25. Our results provide a potential synaptic mechanism through GirK channels to oppose Aβ synaptic, network and cognitive hippocampal dysfunctions
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