Colchicine-induced Deafferentation of the Hippocampus Selectively Disrupts Cholinergic Rhythmical Slow Wave Activity

It has been proposed that hippocampal rhythmical slow wave activity (RSA or theta-rhythm) induced by sensory stimulation (atropine-sensitive theta) is generated by the cholinergic septo-hippocampal system. Although ablations of the septum or its projections to the hippocampus disrupt hippocampal RSA, such non-selective lesions damage both cholinergic and non-cholinergic septo-hippocampal inputs. The present study assesses the effects of a selective septal neurotoxic lesion on hippocampal electrical activity. Colchicine, which has been reported to be selectively toxic to cholinergic neurons in the medial septum, was injected into the right lateral ventricle, and electrodes were implanted bilaterally into the dorsal hippocampus of female Sprague-Dawley rats. Hippocampal electrical activity was recorded 10-14 days later from the ipsilateral (colchicine-treated) and contralateral (control) hemispheres during locomotor activity or immobility. RSA ranging from 6.3 to 8.7 Hz was evoked in both hippocampi during mobility. Following i.p. administration of an anesthetic dose of urethane, hippocampal RSA at a frequency of 4 Hz could be elicited in the control hemisphere (n = 12) of all animals by pinching the tail. RSA was absent in 6 of 9 animals in the colchicine-treated hemisphere. RSA from control and treated hemispheres persisting after urethane administration was abolished by 5 mg/kg of scopolamine, thus verifying its cholinergic nature. A decrease in the number of choline acetyltransferase (ChAT)-immunoreactive neurons in the medial septum and a depletion of acetylcholinesterase (AChE)-staining in the hippocampus were evident in the hemisphere ipsilateral to colchicine administration. These data support the septal pacemaker hypothesis of hippocampal theta-rhythm and further demonstrate the neurotoxic effect of colchicine on septo-hippocampal cholinergic neurons by the induction of a functional alteration. The selective disruption of cholinergic neurons in the medial septum by colchicine provides a means to dissociate the contribution of septal cholinergic and non-cholinergic components to hippocampal electrical activity.