Selective Cholinergic Depletion in Medial Septum Leads to Impaired Long Term Potentiation and Glutamatergic Synaptic Currents in the Hippocampus

Abstract

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.

Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation

“…The molecular mechanisms related to the deficit in LTP in VAChT-deficient mice are not understood but might be related to modification of downstream signaling cascades that contribute to the induction of NMDARdependent synaptic plasticity. Although some studies showed no alteration in LTP after cholinergic degeneration (13), the results presented here agree with other experiments showing regulation of LTP by cholinergic neurotransmission in vivo (7) and in slices (6,8). These findings support the importance of using genetargeting based strategies in studying cholinergic neurotransmission and avoid the inconsistency seen when using immunolesion methods.…”

“…Although cholinergic denervation has been shown in some studies to affect LTP (6)(7)(8)(9), in others decreased cholinergic tone did not affect synaptic plasticity (13). We attribute these differences to variability of lesion-based strategies.…”

“…The basal forebrain cholinergic system, which innervates the hippocampus and cortex, has been suggested to modulate LTP in the hippocampus (6)(7)(8)(9) and has been implicated in many forms of behavior (10). In addition, spatial memory has also been suggested to depend on cholinergic activity (10), although there are numerous controversies surrounding which behaviors acetylcholine (ACh) regulates (11,12).…”

An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3-CA1 synapses in the hippocampus of adult rats

“…In accord with these observations, cholinergic lesion of the medial septum using 192-saporin has been shown to impair long-term potentiation (LTP), a putative cellular correlate of learning and memory, although some studies report no effect of septal lesion on LTP magnitude . Also, 192-saporin-induced septal lesion reduces glutamatergic synaptic currents in CA1 pyramidal cells (Kanju et al 2012), and other septohippocampal lesion studies in rodent brain produce memory and attentional deficits (Bartus et al 1982;Berger-Sweeney et al 2001;Callahan et al 1993;Dekker et al 1991;Drachman and Leavitt 1974;Fibiger 1991;Gold 2003;Nilsson et al 1992;Perry et al 1999;Sarter and Parikh 2005;Wrenn et al 1999). In genetically engineered animals lacking M 1 mAChRs, impaired LTP is evident (Seeger et al 2004;Shinoe et al 2005), as are impairments in spatial memory and consolidation, although deficits in these animals appear to encompass specific tasks rather than broadly disrupting all hippocampus-dependent learning (Anagnostaras et al 2003;Hamilton et al 2001;Miyakawa et al 2001).…”

Hippocampal Cholinergic Neurostimulating Peptide as a Possible Modulating Factor Against Glutamatergic Neuronal Disability by Amyloid Oligomers

“…[20][21][22] Our next question was whether the cholinergic modulating system plays an important role in the enhancement of LTP resulting from single and double TS. To examine the difference in cholinergic modulation depending on the degree of glutamatergic preconditioning on LTP, we investigated the cholinergic modulating effect by continuous application of CCh (50 nM) from 15 min before LTP induction by single TS to 5 min after LTP induction.…”