Degeneration of septohippocampal cholinergic neurons results in memory deficits attributable to loss of cholinergic modulation of hippocampal synaptic circuits. A remarkable consequence of cholinergic degeneration is the sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. The functional impact of sympathetic ingrowth on synaptic physiology has never been investigated. Here, we report that, at CA3-CA1 synapses, a Hebbian form of long-term depression (LTD) induced by muscarinic M 1 receptor activation (mLTD) is lost after medial septal lesion. Unexpectedly, expression of mLTD is rescued by sympathetic sprouting. These effects are specific because LTP and other forms of LTD are unaffected. The rescue of mLTD expression is coupled temporally with the reappearance of cholinergic fibers in hippocampus, as assessed by the immunostaining of fibers for VAChT (vesicular acetylcholine transporter). Both the cholinergic reinnervation and mLTD rescue are prevented by bilateral superior cervical ganglionectomy, which also prevents the noradrenergic sympathetic sprouting. The new cholinergic fibers likely originate from the superior cervical ganglia because unilateral ganglionectomy, performed when cholinergic reinnervation is well established, removes the reinnervation on the ipsilateral side. Thus, the temporal coupling of the cholinergic reinnervation with mLTD rescue, together with the absence of reinnervation and mLTD expression after ganglionectomy, demonstrate that the autonomic-driven cholinergic reinnervation is essential for maintaining mLTD after central cholinergic cell death. We have discovered a novel phenomenon whereby the autonomic and central nervous systems experience structural rearrangement to replace lost cholinergic innervation in hippocampus, with the consequence of preserving a form of LTD that would otherwise be lost as a result of cholinergic degeneration.

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 ␣1 receptors induces activity-and NMDA receptor-dependent long-term depression (LTD) at CA3-CA1 synapses 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␣q-coupled signaling pathway for their induction, and investigated the net effect of coactivation of M 1 and ␣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 signalregulated protein kinase (ERK) activation. Interestingly, LTD can be induced when M 1 and ␣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 ␣1 receptors could function to induce long-term changes in synaptic function important for cognition.

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Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) plaques, hyperphosphorylated tau neurofibrillary tangles (NFTs) and cholinergic dysfunction. Cholinergic degeneration can be mimicked in rats by lesioning cholinergic neurons in medial septum. Hippocampal cholinergic denervation disrupts retrograde transport of nerve growth factor (NGF), leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Previously we reported that coincident with noradrenergic sprouting is the partial reinnervation of hippocampus with cholinergic fibers, and the maintenance of a M1 mAChR dependent long-term depression at CA3-CA1 synapses that is lost in the absence of sprouting. These findings suggest that sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. Interestingly, noradrenergic sympathetic and cholinergic sprouting have been demonstrated in AD postmortem human brain. Furthermore, M1 mAChRs have been a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid beta-protein precursor (AβPP). Here we tested the hypothesis that noradrenergic sympathetic sprouting and the associated increase in cholinergic innervation maintains non-amyloidogenic AβPP processing that is dependent upon M1 mAChRs. Also, we investigated the effect of intrahippocampal Aβ42 infusion on noradrenergic sympathetic and cholinergic sprouting. We found that Aβ42 is not only toxic to central cholinergic fibers innervating hippocampus but prevents and reverses noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation. These findings reiterate the clinical implications of sprouting as an innate compensatory mechanism and emphasize the importance of M1 mAChRs as an AD therapeutic target.