Sympathetic Sprouting Drives Hippocampal Cholinergic Reinnervation That Prevents Loss of a Muscarinic Receptor-Dependent Long-Term Depression at CA3–CA1 Synapses

Abstract

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.

Coactivation of M1Muscarinic and α1 Adrenergic Receptors Stimulates Extracellular Signal-Regulated Protein Kinase and Induces Long-Term Depression at CA3–CA1 Synapses in Rat Hippocampus

“…Additionally, we have shown that mLTD requires activation of M 1 mAChRs; it can be induced using the selective M 1 receptor agonist McN-A-343 (50 M) and prevented by the selective M 1 toxin MTx-7 (100 nM) (Scheiderer et al, 2006). Note the larger transient depression occurring during CCh application compared with during application of Methox.…”

“…Baseline transmission was acquired using 0.2 Hz (100 s duration) stimulation frequency and the stimulus intensity was adjusted to generate a fEPSP of 0.8 -1.0 mV in amplitude. After acquisition of a stable baseline of transmission (at least 20 min), agonists were bath applied to induce LTD. mLTD was induced via a 10 min application of carbachol (CCh) (50 M) or the selective M 1 agonist [4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium] (McN-A-343) (50 M) (adapted from Kirkwood et al, 1999; see also Scheiderer et al, 2006) and NE LTD was induced by a 10 min bath application of the ␣1 agonist methoxamine (Methox; 40 M) (Scheiderer et al, 2004(Scheiderer et al, , 2006. Receptor antagonists and inhibitors of the signaling molecules were bath applied at least 10 min before application of agonists to induce LTD.…”

“…After a 1 h recovery period (as for electrophysiological recordings), the slices were placed in an oxygenated bath (at 28 -30°C) that contained either aCSF alone, or agonists with or without antagonists, conditions that will either induce or prevent induction of mLTD or NE LTD. Induction of both mLTD and NE LTD requires presynaptic activity (i.e., activation of CA3 axons) (Scheiderer et al, 2004(Scheiderer et al, , 2006. However, when the CA3 region remains intact in the slice, LTD is induced in the absence of electrical stimulation, because agonist application causes oscillatory activity in CA3 pyramidal cells.…”

“…We reported previously and show here in Figure 1, A and B, that a 10 min application of either CCh (50 M), a broad spectrum cholinergic agonist, or Methox, an ␣1 adrenergic agonist (40 M), induces LTD at CA3-CA1 synapses recorded in acutely prepared hippocampal slices (CCh: 76 Ϯ 2% of baseline fEPSP slope, n ϭ 7, p Ͻ 0.05; Methox: 87 Ϯ 5% of baseline fEPSP slope, n ϭ 4, p Ͻ 0.05); we have termed these plasticities mLTD and NE LTD (Scheiderer et al, 2006). Additionally, we have shown that mLTD requires activation of M 1 mAChRs; it can be induced using the selective M 1 receptor agonist McN-A-343 (50 M) and prevented by the selective M 1 toxin MTx-7 (100 nM) (Scheiderer et al, 2006).…”

“…We reported previously that activation of muscarinic M 1 or adrenergic ␣l receptors induces long-term depression (LTD) of synaptic transmission at excitatory CA3-CA1 synapses in acute slices of rat hippocampus; we refer to these forms of LTD as muscarinic LTD (mLTD) (Scheiderer et al, 2006) and norepinephrine LTD (NE LTD) (Scheiderer et al, 2004), respectively. Both mLTD and NE LTD require presynaptic activity and NMDA receptor (NMDAR) activation, indicating that they share mechanistic properties.…”