Abstract
Disinhibition-mediated long-term potentiation (LTP) in the CA1 region of the hippocampus involves GABAergic synaptic plasticity at feedforward inhibitory inputs, resulting in the reduced shunting of glutamatergic excitatory currents. The GABAergic plasticity which underlies disinhibition-mediated LTP results from a Ca2+-dependent decrease in the activity of the K+–Cl− cotransporter (KCC2), depolarizing the reversal potential for GABAA receptor-mediated currents (EGABA), thereby attenuating inhibition. Muscarinic acetylcholine receptor (mAChR) activation has previously been shown to regulate classic glutamatergic LTP, modulate intracellular [Ca2+] and signaling, and facilitate the excitability of GABAergic interneurons in the CA1. Based on these effects, and the ability of mAChR activation to regulate CA1 pyramidal neuron KCC2 expression, we proposed that mAChR activation would modulate disinhibition-mediated LTP. To test this prediction, we made whole cell recordings from CA1 pyramidal neurons in hippocampal slices. Disinhibition-mediated LTP was induced using a spike timing-dependent plasticity (STDP) protocol, which involved coincident pre-synaptic stimulation and post-synaptic current injection (at 5 Hz for 60 s). We found that mAChR activation via carbachol (CCh) prevented the induction of disinhibition-mediated LTP. Moreover, in the presence of CCh, EGABA failed to depolarize following plasticity induction. Lastly, we recorded the paired-pulse ratio (PPR) during the induction of disinhibition-mediated LTP and found that in the presence of CCh, plasticity induction induced a significant paired-pulse depression. This suggests that pre-synaptic mAChR activation may prevent the post-synaptic expression of disinhibition-mediated LTP.
Highlights
Long-term potentiation (LTP) is mostly studied at glutamatergic synapses onto pyramidal neurons, and is the leading cellular model of learning and memory (Malinow et al, 2000; Malenka, 2003; Lynch, 2004)
MAChR ACTIVATION DOES NOT REGULATE EGABA Our main objective was to determine whether Muscarinic acetylcholine receptor (mAChR) activation modulates disinhibition-mediated LTP in the CA1 region of the hippocampus
Because the mechanism underlying disinhibition-mediated LTP is a depolarization of the reversal potential for post-synaptic potentials (PSPs) (Erev), which results from a depolarization of the reversal potential for inhibitory GABAA receptor-mediated currents (EGABA) (Woodin et al, 2003; Ormond and Woodin, 2009, 2011; Lamsa et al, 2010), we first had to determine whether mAChR activation alone modulates EGABA
Summary
Long-term potentiation (LTP) is mostly studied at glutamatergic synapses onto pyramidal neurons, and is the leading cellular model of learning and memory (Malinow et al, 2000; Malenka, 2003; Lynch, 2004). This classic glutamatergic LTP depends on NMDA receptor activation, and results from AMPA receptor phosphorylation and an increase in their post-synaptic membrane expression. During learning and memory processing, neuronal circuits in the hippocampus are modified by neuromodulators that regulate synaptic plasticity (Parent and Baxter, 2004; Giocomo and Hasselmo, 2007).
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