Muscarinic acetylcholine receptor knockout mice show distinct synaptic plasticity impairments in the visual cortex

In the present report, we focused our attention on the role played by the muscarinic acetylcholine receptors (mAChRs) in different forms of long-term synaptic plasticity. Specifically, we investigated long-term potentiation (LTP) and long-term depression (LTD) expression elicited by theta-burst stimulation (TBS) and low-frequency stimulation (LFS), respectively, in visual cortical slices obtained from different mAChR knockout (KO) mice. A normal LTP was evoked in M(1)/M(3) double KO mice, while LTP was impaired in the M(2)/M(4) double KO animals. On the other hand, LFS induced LTD in M(2)/M(4) double KO mice, but failed to do so in M(1)/M(3) KO mice. Interestingly, LFS produced LTP instead of LTD in M(1)/M(3) KO mice. Analysis of mAChR single KO mice revealed that LTP was affected only by the simultaneous absence of both M(2) and M(4) receptors. A LFS-dependent shift from LTD to LTP was also observed in slices from M(1) KO mice, while LTD was simply abolished in slices from M(3) KO mice. Using pharmacological tools, we showed that LTP in control mice was blocked by pertussis toxin, an inhibitor of G(i/o) proteins, but not by raising intracellular cAMP levels. In addition, the inhibition of phospholipase C by U73122 induced the same shift from LTD to LTP after LFS observed in M(1) single KO and M(1)/M(3) double KO mice. Our results indicate that different mAChR subtypes regulate different forms of long-term synaptic plasticity in the mouse visual cortex, activating specific G proteins and downstream intracellular mechanisms.