Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation

Gil-Bea, Francisco J.; Solas, Maite; Mateos, Laura; Winblad, Bengt; Ramı́rez, Marı́a J.; Cedazo-Mı́nguez, Ángel

doi:10.1002/hipo.20812

Cited by 50 publications

(36 citation statements)

References 49 publications

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“…This is consistent with previous studies showing that a complete lesion of BFCNs in rats resulted in reduced BDNF mRNA in the hippocampus (Kokaia et al, 1996, Ferencz et al, 1997, Berchtold et al, 2002 and that cholinergic basal forebrain innervation of hippocampus is involved in the regulation of BDNF protein and mRNA (Lapchak et al, 1993, Gil-Bea et al, 2011. BDNF is synthesized, stored and released from dendrites of most excitatory neurons including pyramidal neurons in the hippocampus, in an activity-dependent manner (Hartmann et al, 2001).…”

Section: Discussionsupporting

confidence: 91%

“…ACh mediates hippocampal learning and memory through regulation of long-term potentiation (LTP) and synaptic consolidation (Auerbach and Segal, 1994, Ovsepian et al, 2004, Drever et al, 2011. Moreover, ACh is a presynaptic modulator of hippocampal excitatory transmission, promoting long-term synaptic plasticity and upregulating brain-derived neurotrophic factor (BDNF) protein and Arc expression in the hippocampus, which are involved in synaptic consolidation (Fernandez de Sevilla et al, 2008, Gil-Bea et al, 2011. Thus ACh signalling from the cholinergic basal forebrain to the hippocampus is vital for hippocampal function and normal cognition, and deterioration of this brain structure in human disease, not surprisingly, has devastating consequences.…”

Section: The Cholinergic Basal Forebrainmentioning

confidence: 99%

“…Reduced cholinergic signalling has been shown to affect the expression and processing of APP, for example loss of subcortical cholinergic innervation induces cortical APP mRNA and increased levels of secreted APP into the cerebrospinal fluid (CSF) (Wallace andHaroutunian, 1993, Schliebs, 2005). Futhermore, induced cholinergic hypofunction results in downregulation of BDNF (Gil-Bea et al, 2011), a member of the neurotrophin family which has been shown to be directly involved in the regulation of AD pathology.…”

Section: Cholinergic Hypofunction In Alzheimer's Diseasementioning

confidence: 99%

“…This BDNF acts in an autocrine manner through its receptor, TrkB, to trigger synthesis of dendritic proteins and modulate LTP, thus impacting on the molecular machinery of memory consolidation in the hippocampus (Hartmann et al, 2001, Gil-Bea et al, 2011. In a mouse model of cholinergic hypofunction, the loss of BFCN projections that stimulate activity-dependent neurotrophin release contributes to the selective decrease in BDNF protein and consequent dysregulation of downstream signalling in the hippocampus (Gil-Bea et al, 2011).…”

Section: Neurotrophic Function In the Hippocampusmentioning

confidence: 99%

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Neurotrophin regulation of Alzheimer's disease pathology

Turnbull¹

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Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized histopathologically by the accumulation of amyloid-β (Aβ) and hyperphosphorylation of tau protein. These two key proteins are major contributors to neuronal toxicity and disease progression; however, the causal factors initiating this toxic cascade in sporadic disease are unknown. We hypothesize that the specific degeneration of basal forebrain cholinergic neurons (BFCNs) and a decrease in neurotrophin availability -which occur coincidentally with the disease -are key regulators of aberrant Aβ accumulation and tau hyperphosphorylation, and could constitute the molecular basis of AD pathology in sporadic disease. Here we show that loss of BFCN innervation to the hippocampus of two pre-symptomatic mouse lines modelling the disease (APP/PS1 and pR5 (P301L) mice) causes a reduction in hippocampal and nerve growth factor (NGF) protein and/or brain-derived neurotrophic factor (BDNF). In APP/PS1 mice this correlates with memory and learning deficits in a Morris water maze task, which is not observed in unlesioned transgenic controls and wildtype littermates -indicating an exacerbation of the disease. Loss of BFCN hippocampal innervation in APP/PS1 mice also increases the amount of total Aβ in the hippocampus, but has no additional effects on levels of tau hyperphosphorylation. In contrast, memory deficits are not observed in pR5 tau transgenic mice following an equivalent loss of BFCN hippocampal innervation and reduction of neurotrophin levels. Moreover, hippocampal levels of tau and hyperphosphorylated tau were comparable to that of control pR5 tau transgenic mice. The role of neurotrophins in Aβ pathology in APP/PS1 mice was further assessed through viral knockdown of BDNF protein in the hippocampus, and treatment with a neurotrophic c29 peptide following loss of basal forebrain cholinergic neurons. Although reduction of BDNF did not cause increased Aβ levels, and treatment with c29 peptide did not reduce Aβ load in the hippocampus of APP/PS1 mice following loss of BFCN, c29 peptide was able to rescue behavioural deficits of aged unlesioned APP/PS1 mice.This work demonstrates that early cholinergic denervation of the hippocampus can trigger some features of Alzheimer's disease, namely reduced neurotrophin expression and increased Aβ production, but does not alone cause tau hyperphosphorylation and aggregation. These results are consistent with the idea that tau pathology in AD may be downstream of Aβ pathology, and highlights the possibility that cholinergic dysfunction might be a major upstream contributing factor of sporadic Alzheimer's disease. Although we show that neurotrophin dysfunction is insufficient by itself to induce or prevent Aβ accumulation, enhancing neurotrophic signalling to provide cognitive benefit may be a viable treatment strategy.

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Section: Discussionsupporting

confidence: 91%

Section: The Cholinergic Basal Forebrainmentioning

confidence: 99%

Section: Cholinergic Hypofunction In Alzheimer's Diseasementioning

confidence: 99%

Section: Neurotrophic Function In the Hippocampusmentioning

confidence: 99%

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Neurotrophin regulation of Alzheimer's disease pathology

Turnbull¹

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“…Initiated by the pioneering work of MacIntosh and Oboring (1955), which demonstrated that ACh controls the neuronal excitability, the interest in the function of the cholinergic system greatly increased with the characterization of cholinergic antagonists as impairment agents of cognitive abilities (Deutsch, 1971;Drachman, 1977) and with the postmortem identification of reduced cholinergic markers in the brain of Alzheimer's disease patients (Bowen et al, 1976;Perry et al, 1978). The cholinergic drive controls a large variety of cognitive processes, such as attention (Hasselmo and Sarter, 2011), learning (Fine et al, 1997;Miranda and Bermú dez-Rattoni, 1999), and memory (Hasselmo and Bower, 1992;Gil-Bea et al, 2010) by boosting the signal-to-noise ratio (Sillito and Kemp, 1983) in various cortical and subcortical nuclei entrained within a complex neuronal network (Everitt and Robbins, 1997). The mutually interacting PFC and hippocampus (Hipp) represent the core of this network involved in cognitive processing (GoldmanRakic, 1995;Thierry et al, 2000;Warburton and Brown, 2010).…”

Section: Introductionmentioning

confidence: 99%

Cholinergic Control in Developing Prefrontal–Hippocampal Networks

Janiesch¹,

Krüger²,

Poschel³

et al. 2011

J. Neurosci.

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The cholinergic drive enhances input processing in attentional and mnemonic context by interacting with the activity of prefrontalhippocampal networks. During development, acetylcholine modulates neuronal proliferation, differentiation, and synaptic plasticity, yet its contribution to the maturation of cognitive processing resulting from early entrainment of neuronal networks in oscillatory rhythms remains widely unknown. Here we show that cholinergic projections growing into the rat prefrontal cortex (PFC) toward the end of the first postnatal week boost the generation of nested gamma oscillations superimposed on discontinuous spindle bursts by acting on functional muscarinic but not nicotinic receptors. Although electrical stimulation of cholinergic nuclei increased the occurrence of nested gamma spindle bursts by 41%, diminishment of the cholinergic input by either blockade of the receptors or chronic immunotoxic lesion had the opposite effect. This activation of locally generated gamma episodes by direct cholinergic projections to the PFC was accompanied by indirect modulation of underlying spindle bursts via cholinergic control of hippocampal theta activity. With ongoing maturation and switch of network activity from discontinuous bursts to continuous theta-gamma rhythms, accumulating cholinergic projections acting on both muscarinic and nicotinic receptors mediated the transition from high-amplitude slow to low-amplitude fast rhythms in the PFC. By exerting multiple actions on the oscillatory entrainment of developing prefrontal-hippocampal networks, the cholinergic input may refine them for later gating processing in executive and mnemonic tasks.

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Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

Koola

2020

Human Psychopharmacology

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Development of novel treatments for positive, cognitive, and negative symptoms continue to be a high‐priority area of schizophrenia research and a major unmet clinical need. Given that all randomized controlled trials (RCTs) conducted to date failed with one add‐on medication/mechanism of action, future RCTs with the same approach are not warranted. Even if the field develops a medication for cognition, others are still needed to treat negative and positive symptoms. Therefore, fixing one domain does not completely solve the problem. Also, targeting the cholinergic system, glutamatergic system, and cholinergic plus alpha7 nicotinic and N‐methyl‐D‐aspartate (NMDA) receptors failed independently. Hence, targeting other less important pathophysiological mechanisms/targets is unlikely to be successful. Meta‐analyses of RCTs targeting major pathophysiological mechanisms have found some efficacy signal in schizophrenia; thus, combination treatments with different mechanisms of action may enhance the efficacy signal. The objective of this article is to highlight the importance of conducting RCTs with novel combination treatments in schizophrenia to develop antischizophrenia treatments. Positive RCTs with novel combination treatments that target the alpha7 nicotinic and NMDA receptors simultaneously may lead to a disease‐modifying therapeutic armamentarium in schizophrenia. Novel combination treatments that concurrently improve the three domains of psychopathology and several prognostic and theranostic biomarkers may facilitate therapeutic discovery in schizophrenia.

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Cholinergic hypofunction impairs memory acquisition possibly through hippocampal Arc and BDNF downregulation

Cited by 50 publications

References 49 publications

Neurotrophin regulation of Alzheimer's disease pathology

Neurotrophin regulation of Alzheimer's disease pathology

Cholinergic Control in Developing Prefrontal–Hippocampal Networks

Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

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