Muscarinic receptor loss and preservation of presynaptic cholinergic terminals in hippocampal sclerosis

Purpose: Prior single-photon emission tomography studies showed losses of m uscarinic acetylcholine receptor (MAChR) binding in patients with refractor y mesial temporal lobe epilepsy. Experimental animal studies demonstrated t ransient losses of MAChR due to electrically induced seizures originating i n the amygdala. However, the relations between cholinergic synaptic markers , seizures, and underlying neuropathology in human temporal lobe epilepsy a re unknown. We tested the hypotheses that human brain MAChR changes are att ributable to hippocampal sclerosis (HS), and that HS resembles axon-sparing lesions in experimental animal models. Methods: We measured MAChR binding-site density, an intrinsic neuronal mark er, within the hippocampal formation (I-IF) in anterior temporal lobectomy specimens from 10 patients with HS and in 10 autopsy controls. Binding-site density of the presynaptic vesicular acetylcholine transporter (VAChT) was measured as a marker of extrinsic cholinergic afferent integrity. MAChR an d VAChT results were compared with neuronal cell counts to assess their rel ations to local neuronal losses. Results: Reduced MAChR binding-site density was demonstrated throughout the HF in the epilepsy specimens compared with autopsy controls and correlated in severity with reductions in cell counts in several HF regions. In contr ast to MAChR, VAChT binding-site density was unchanged in the epilepsy spec imens compared with autopsy controls. Conclusions: Reduction in MAChR binding in HS is attributable to intrinsic neuronal losses. Sparing of afferent septal cholinergic terminals is consis tent with the hypothesis that an excitotoxic mechanism may contribute to th e development of HS and refractory partial epilepsy in humans.