Cholinergic function and memory: Extensive inhibition of choline acetyltransferase fails to impair radial maze performance in rats

Wenk, Gary L.; Sweeney, Joanne E.; Hughey, Donna; Carson, James Taylor; Olton, David S.

doi:10.1016/0091-3057(86)90134-6

Cited by 26 publications

(8 citation statements)

References 50 publications

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“…In mice treated with the ChAT inhibitor 4-(1-naphtylvinyl)pyridine (NVP) (250 mg/kg), a 60% drop in ChAT activity resulted in a 20% reduction of brain ACh levels after swimming stress (Krell and Goldberg, 1975), whereas in an analogous experiment in rats, NVP (200 mg/kg) caused a reduction in brain ACh levels by 90% (Budai et al, 1986). In rats treated with the ChAT inhibitor BW813U, a 60% reduction of ChAT activity did not impair performance on a previously learned spatial task (the rate of acquisition was not tested) (Wenk et al, 1986). Clinical evidence indicates that the threshold beyond which reduced ChAT activity causes functional impairments is quite close to 50%.…”

Section: Discussionmentioning

confidence: 98%

Choline Transporter 1 Maintains Cholinergic Function in Choline Acetyltransferase Haploinsufficiency

Brandon¹,

Mellott²,

Pizzo³

et al. 2004

J. Neurosci.

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Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons. The rate-limiting factor in ACh production is the provision of choline to ChAT. Cholinergic neurons are relatively unique in their expression of the choline transporter 1 (CHT1), which exhibits high-affinity for choline and catalyzes its uptake from the extracellular space to the neuron. Multiple lines of evidence indicate that the activity of CHT1 is a key determinant of choline supply for ACh synthesis. We examined the interaction of ChAT and ChT activity using mice heterozygous for a null mutation in the Chat gene (Chatϩ/Ϫ). In these mice, brain ChAT activity was reduced by 40 -50% relative to the wild type, but brain ACh levels as well as ACh content and depolarization-evoked ACh release in hippocampal slices were normal. However, the amount of choline taken up by CHT1 and ACh synthesized de novo from choline transported by CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1 protein in several regions of the CNS, were 50 -100% higher in Chatϩ/Ϫ than in Chatϩ/ϩ mice. Thus, haploinsufficiency of ChAT leads to an increased expression of CHT1. Increased ChT activity may compensate for the reduced ChAT activity in Chatϩ/Ϫ mice, contributing to the maintenance of apparently normal cholinergic function as reflected by normal performance of these mice in several behavioral assays.

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Section: Discussionmentioning

confidence: 98%

Choline Transporter 1 Maintains Cholinergic Function in Choline Acetyltransferase Haploinsufficiency

Brandon¹,

Mellott²,

Pizzo³

et al. 2004

J. Neurosci.

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“…The assessment was based on performance of rats on custom-made wooden radial arm maze (RAM), a paradigm that has been used for testing spatial working and reference memory (Olton and Samuelson 1976; Olton 1985; Wenk et al 1986). The assessment was carried out in two phases, namely; working (short-term) memory (defined as information that is useful to the rat during the current experience with the task) and reference (long-term) memory (information that is useful in all exposures to the task across all the days of testing) (Olton 1985; Wenk et al 1986).…”

Section: Methodsmentioning

confidence: 99%

“…The assessment was carried out in two phases, namely; working (short-term) memory (defined as information that is useful to the rat during the current experience with the task) and reference (long-term) memory (information that is useful in all exposures to the task across all the days of testing) (Olton 1985; Wenk et al 1986). Short-term (working) memory was tested for 8 consecutive days with one trial per day that was preceded by 3 days of habituation (15 min trial per day).…”

Section: Methodsmentioning

confidence: 99%

Memory deficits associated with sublethal cyanide poisoning relative to cyanate toxicity in rodents

et al. 2013

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Background Food (cassava) linamarin is metabolized into neurotoxicants cyanide and cyanate, metabolites of which we sought to elucidate the differential toxicity effects on memory. Methods Young 6-8 weeks old male rats were treated intraperitoneally with either 2.5 mg/kg body weight (bw) cyanide (NaCN), or 50 mg/kg bw cyanate (NaOCN), or 1 μl/g bw saline, daily for 6 weeks. Short-term and long-term memories were assessed using a radial arm maze (RAM) testing paradigm. Results Toxic exposures had an influence on short-term working memory with fewer correct arm entries (F 2, 19 = 4.57 p <0.05), higher working memory errors (WME) (F 2, 19 = 5.09, p <0.05) and longer RAM navigation time (F2, 19 = 3.91, p <0.05) for NaOCN relative to NaCN and saline treatments. The long-term working memory was significantly impaired by cyanide with fewer correct arm entries (F 2, 19 = 7.45, p <0.01) and increased working memory errors (F 2, 19 = 9.35 p <0.05) in NaCN relative to NaOCN or vehicle treated animals. Reference memory was not affected by either cyanide or cyanate. Conclusion Our study findings provide an experimental evidence for the biological plausibility that cassava cyanogens may induce cognition deficits. Differential patterns of memory deficits may reflect the differences in toxicity mechanisms of NaOCN relative to NaCN. Cognition deficits associated with cassava cyanogenesis may reflect a dual toxicity effect of cyanide and cyanate.

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“…In early studies it was believed that NBM cholinergic neurons were involved in learning and memory due to impairments seen when excitatory amino acid lesions were used [41]. However these effects are believed to be attributed to performance decrements, as the use of a selective ChAT inhibitor, which significantly reduced ACh levels in the brain, did not impair ability in the radial arm maze task [42]. Through the use of temporal discrimination tasks [43] and the detection of brief sensory stimuli it has been hypothesized that NBM neurons may be important in aspects of attention [44].…”

Section: Basal Forebrain Cholinergic Neuronsmentioning

confidence: 99%

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

Kwakowsky

Milne

Waldvogel

et al. 2016

IJMS

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The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2) on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease.

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Cholinergic function and memory: Extensive inhibition of choline acetyltransferase fails to impair radial maze performance in rats

Cited by 26 publications

References 50 publications

Choline Transporter 1 Maintains Cholinergic Function in Choline Acetyltransferase Haploinsufficiency

Choline Transporter 1 Maintains Cholinergic Function in Choline Acetyltransferase Haploinsufficiency

Memory deficits associated with sublethal cyanide poisoning relative to cyanate toxicity in rodents

Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

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