Coactivation of m1 muscarinic and α1 adrenergic receptors stimulates extracellular signal-regulated protein kinase and induces long-term depression at CA3-CA1 Synapses in rat hippocampus

Intact cholinergic innervation from the medial septum and noradrenergic innervation from the locus ceruleus are required for hippocampal-dependent learning and memory. However, much remains unclear about the precise roles of acetylcholine (ACh) and norepinephrine ( NE) in hippocampal function, particularly in terms of how interactions between these two transmitter systems might play an important role in synaptic plasticity. Previously, we reported that activation of either muscarinic M-1 or adrenergic alpha 1 receptors induces activity- and NMDA receptor-dependent long-term depression (LTD) atCA3-CA1synapses in acute hippocampal slices, referred to as muscarinic LTD (mLTD) and norepinephrine LTD ( NE LTD), respectively. In this study, we tested the hypothesis that mLTD and NE LTD are independent forms of LTD, yet require activation of a common G alpha q-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M-1 and alpha 1 receptors on the magnitude of LTD induced. We find that neither mLTD nor NE LTD requires phospholipase C activation, but both plasticities are prevented by inhibiting the Src kinase family and extracellular signal-regulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M-1 and alpha 1 agonists are coapplied at concentrations too low to induce LTD when applied separately, via a summed increase in ERK activation. Thus, because ACh and NE levels in vivo covary, especially during periods of memory encoding and consolidation, cooperative signaling through M-1 and alpha 1 receptors could function to induce long-term changes in synaptic function important for cognition.