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The Journal of Neuroscience, April 5, 2006, 26(14):3745-3756; doi:10.1523/JNEUROSCI.5507-05.2006

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

Cary L. Scheiderer,² Eve McCutchen,¹ Erin E. Thacker,¹ Krystyna Kolasa,^3,4 Matthew K. Ward,⁵ Dee Parsons,^3,4 Lindy E. Harrell,^3,4,6 Lynn E. Dobrunz,^1,2,3 and Lori L. McMahon^1,2,3

Departments of ¹Physiology and Biophysics and ²Neurobiology, ³Alzheimer's Disease Research Center, Departments of ⁴Neurology and ⁵Psychology, and ⁶Veterans Affairs Medical Center, University of Alabama at Birmingham, Birmingham, Alabama 35294

Correspondence should be addressed to Dr. Lori L. McMahon, Department of Physiology and Biophysics, University of Alabama at Birmingham, 1918 University Boulevard, MCLM 964, Birmingham, AL 35294-0005. Email: mcmahon{at}physiology.uab.edu

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 M₁ 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.

Key words: synaptic plasticity; hippocampus; LTD; muscarinic acetylcholine receptor; G-protein-coupled receptors; superior cervical ganglion

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Received Aug. 3, 2005; revised Feb. 7, 2006; accepted Feb. 7, 2006.

Correspondence should be addressed to Dr. Lori L. McMahon, Department of Physiology and Biophysics, University of Alabama at Birmingham, 1918 University Boulevard, MCLM 964, Birmingham, AL 35294-0005. Email: mcmahon{at}physiology.uab.edu

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