Acetylcholinesterase Inhibitors Activate Septohippocampal GABAergic Neurons via Muscarinic but Not Nicotinic Receptors

Wu, Min; Newton, Samuel S.; Atkins, Joshua B.; Xu, Changqing; Duman, Ronald S.; Alreja, Meenakshi

doi:10.1124/jpet.103.052514

Cited by 36 publications

(38 citation statements)

References 42 publications

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“…Thus, , which is a conjugate of the fluorochrome Cy3, and an antibody (Ab) against the p75 receptor (192IgG), is taken up only by cholinergic terminals and thus selectively labels only the cholinergic subpopulation. The specificity of this marker and its inert nature have been thoroughly confirmed in previous studies by us Wu et al, 2000Wu et al, , 2003b and by others (Hartig et al, 1998).…”

Section: Methodssupporting

confidence: 69%

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Wu¹,

Záborszky²,

Hajszán³

et al. 2004

J. Neurosci.

131

101

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Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum-diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics. In the present study, we investigated the electrophysiological effects of Hcrt peptides on septohippocampal cholinergic neurons that were identified in living brain slices of the MSDB using a selective fluorescent marker. Hcrt activation of septohippocampal cholinergic neurons was reversible, reproducible, and concentration dependent and mediated via a direct postsynaptic mechanism. Both Hcrt1 and Hcrt2 activated septohippocampal cholinergic neurons with similar EC 50 values. The Hcrt effect was dependent on external Na ϩ , reduced by external Ba 2ϩ , and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K ϩ current, presumably an inward rectifier, and a Na ϩ -dependent component. The Na ϩ component was dependent on internal Ca 2ϩ , blocked by replacing external Na ϩ with Li ϩ , and also blocked by bath-applied Ni 2ϩ and KB-R7943, suggesting involvement of the Na ϩ -Ca 2ϩ exchanger. Using double-immunolabeling studies at light and ultrastructural levels, we also provide definitive evidence for a hypocretin innervation of cholinergic neurons. Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal.

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Section: Methodssupporting

confidence: 69%

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Wu¹,

Záborszky²,

Hajszán³

et al. 2004

J. Neurosci.

131

101

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“…The mGluR1a has been shown to lie upstream of PLC-␤4 in the medial septum (Nakamura et al, 2004), and mGluR1a antagonists have been shown to decrease the firing rate of both septohippocampal cholinergic and GABAergic neurons in the medial septum (Wu et al, 2003a(Wu et al, , 2004. Interestingly, acetycholinesterase inhibitors have been shown to not only increase the acetylcholine concentration in the hippocampus (Van Dam et al, 2005;Cerbai et al, 2007) but also to enhance GABAergic neuronal firing rate in the medial septum (Wu et al, 2003b). Therefore, administration of an acetylcholine esterase inhibitor to PLC-␤4 Ϫ/Ϫ mice might be expected to recover attenuated cholinergic theta rhythms in the mutant.…”

Section: Discussionmentioning

confidence: 99%

“…To further confirm the interrelationship between cholinergic theta rhythms and anxiety behavior, we designed an experiment to determine whether increasing cholinergic transmission in PLC-␤4 Ϫ/Ϫ mice could rescue the attenuated amplitude of cholinergic theta rhythms, and thereby normalize the attendant anxiety behavior. To this end, we administered the cholinergicenhancing drug, rivastigmine, an acetylcholinesterase inhibitor known to increase the cholinergic transmission in the septohippocampal pathway (Wu et al, 2003b;Van Dam et al, 2005;Cerbai et al, 2007).…”

Section: Rescue Of the Plc-␤4mentioning

confidence: 99%

Phospholipase C β4 in the Medial Septum Controls Cholinergic Theta Oscillations and Anxiety Behaviors

Shin

Gangadharan²,

Kim³

et al. 2009

J. Neurosci.

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Anxiety is among the most prevalent and costly diseases of the CNS, but its underlying mechanisms are not fully understood. Although attenuated theta rhythms have been observed in human subjects with increased anxiety, no study has been done on the possible physiological link between these two manifestations. We found that the mutant mouse for phospholipase C ␤4 (PLC-␤4 Ϫ/Ϫ ) showed attenuated theta rhythm and increased anxiety, presenting the first animal model for the human condition. PLC-␤4 is abundantly expressed in the medial septum, a region implicated in anxiety behavior. RNA interference-mediated PLC-␤4 knockdown in the medial septum produced a phenotype similar to that of PLC-␤4 Ϫ/Ϫ mice. Furthermore, increasing cholinergic signaling by administering an acetylcholinesterase inhibitor cured the anomalies in both cholinergic theta rhythm and anxiety behavior observed in PLC-␤4 Ϫ/Ϫ mice. These findings suggest that (1) PLC-␤4 in the medial septum is involved in controlling cholinergic theta oscillation and (2) cholinergic theta rhythm plays a critical role in suppressing anxiety. We propose that defining the cholinergic theta rhythm profile may provide guidance in subtyping anxiety disorders in humans for more effective diagnosis and treatments.

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“…This lack of adaptation in the hippocampal cholinergic response may be due to the loss of MS/DB cells in the PTD model. There is evidence that both cholinergic and GABAergic cells in the MS/DB modulate neural activation of the hippocampus [1,56,60]. Cholinergic activation in the hippocampus triggers rhythmic activity that can persist for hours and such rhythmic activity is related to both learning and neural plasticity [11].…”

Section: Discussionmentioning

confidence: 99%

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

2007

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A rodent model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), was used to investigate diencephalic-limbic interactions. In-vivo acetylcholine (ACh) efflux, a marker of memory-related activation, was measured in the hippocampus and the amygdala of PTD-treated and pair-fed (PF) control rats while they were tested on a spontaneous alternation task. During behavioral testing, all animals displayed increases in ACh efflux in both the hippocampus and amygdala. However, during spontaneous alternation testing ACh efflux in the hippocampus and the alternation scores were higher in PF rats relative to PTD-treated rats. In contrast, ACh efflux in the amygdala was not suppressed in PTD treated rats, relative to PF rats, prior to or during behavioral testing. In addition, unbiased stereological estimates of the number of choline acetyltransferase (ChAT) immunopositive neurons in the medial septal/diagonal band (MS/DB) and nucleus basalis of Meynert (NBM) also reveal a selective cholinergic dysfunction: In PTD-treated rats a significant loss of ChAT-immunopositive cells was found only in the MS/DB, but not in the NBM. Significantly, these results demonstrate that thiamine deficiency causes selective cholinergic dysfunction in the septohippocampal pathway. Keywords diencephalon; hippocampus; amygdala; microdialysis; acetylcholine; stereology Selective septohippocampal-but not forebrain amygdalarcholinergic dysfunction in diencephalic amnesiaDiencephalic lesions are seen in a range of disorders: malnourishment, ischemic infarcts, viral infections, tumors and traumatic damage. Damage to certain nuclei and fiber systems within the diencephalon interrupts the flow of information between key memory structures and thus causes severe and long-lasting amnesia [25,29,45]. Although there is evidence that lesions to particular diencephalic nuclei result in memory impairment in their own right, there is also evidence that damage to diencephalic nuclei can disrupt memory circuits leading to dysfunction in other regions of the brain [4,29,45,49,53].Corresponding author: Lisa M. Savage, Department of Psychology, Binghamton University, State University of New York, Binghamton, NY, 13902, e-mail: lsavage@binghamton.edu, fax: 607-777-4890. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. At one point, WKS patients were labeled as "temporal lobe-related amnesiacs" based on their memory performance [10]. This clinical population was critical for the development of the memory system classifications (i.e., declarative vs. nondeclarative memory [51]). However, it is clear from...

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Acetylcholinesterase Inhibitors Activate Septohippocampal GABAergic Neurons via Muscarinic but Not Nicotinic Receptors

Cited by 36 publications

References 42 publications

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Phospholipase C β4 in the Medial Septum Controls Cholinergic Theta Oscillations and Anxiety Behaviors

Selective septohippocampal – but not forebrain amygdalar – cholinergic dysfunction in diencephalic amnesia

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