Mice Deficient for the Vesicular Acetylcholine Transporter Are Myasthenic and Have Deficits in Object and Social Recognition

Prado, Vânia F.; Martins-Silva, Cristina; Castro, Braulio M. de; Lima, Ricardo; Barros, Daniela M.; Amaral, Evaldo Pinheiro; Ramsey, Amy J.; Sotnikova, Tatyana D.; Ramirez, Maria Rosana; Kim, Hyunggun; Rossato, Janine I.; Koenen, Janaina; Quan, Hui; Cota, Vinícius Rosa; Moraes, Márcio Flávio Dutra; Gomez, Marcus V.; Guatimosim, Cristina; Wetsel, William C.; Kushmerick, Christopher; Pereira, Grace Schenatto; Gainetdinov, Raul R.; Izquierdo, Iván; Caron, Marc G.; Prado, Marco A. M.

doi:10.1016/j.neuron.2006.08.005

Cited by 215 publications

(311 citation statements)

References 53 publications

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“…Furthermore, iontophoresis of ACH in the neocortex of anesthetized animals (3)(4)(5) produces an increase in amplitude and signal-to-noise ratio (SNR) of evoked sensory responses similar to those occurring after transition from sleep to wakefulness (6). Conversely, experimental lesions of cholinergic neurons in the basal forebrain (7), the major source of neocortical ACH, or genetically induced reduction of ACH release (8) lead to impaired sensory processing.…”

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confidence: 99%

Cholinergic filtering in the recurrent excitatory microcircuit of cortical layer 4

Eggermann

Feldmeyer

2009

Proc. Natl. Acad. Sci. U.S.A.

102

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Neocortical acetylcholine (ACH) release is known to enhance signal processing by increasing the amplitude and signal-to-noise ratio (SNR) of sensory responses. It is widely accepted that the larger sensory responses are caused by a persistent increase in the excitability of all cortical excitatory neurons. Here, contrary to this concept, we show that ACH persistently inhibits layer 4 (L4) spiny neurons, the main targets of thalamocortical inputs. Using whole-cell recordings in slices of rat primary somatosensory cortex, we demonstrate that this inhibition is specific to L4 and contrasts with the ACH-induced persistent excitation of pyramidal cells in L2/3 and L5. We find that this inhibition is induced by postsynaptic M 4 -muscarinic ACH receptors and is mediated by the opening of inwardly rectifying potassium (K ir ) channels. Pair recordings of L4 spiny neurons show that ACH reduces synaptic release in the L4 recurrent microcircuit. We conclude that ACH has a differential layer-specific effect that results in a filtering of weak sensory inputs in the L4 recurrent excitatory microcircuit and a subsequent amplification of relevant inputs in L2/3 and L5 excitatory microcircuits. This layer-specific effect may contribute to improve cortical SNR.

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confidence: 99%

Cholinergic filtering in the recurrent excitatory microcircuit of cortical layer 4

Eggermann

Feldmeyer

2009

Proc. Natl. Acad. Sci. U.S.A.

102

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“…In the present study, we used genetic manipulation of VAChT (20) to investigate the specific contribution of forebrain cholinergic neurotransmission to behavioral manifestations and cellular mechanisms thought to be associated with learning and memory. We report that hippocampal cholinergic deficits caused LTP impairment in the CA1-CA3 pathway.…”

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confidence: 99%

“…Therefore, to investigate the specific roles of ACh in synaptic plasticity, we initially tested whether LTP was affected in VAChT KD HOM mice. For these experiments, we recorded fEPSP in the CA1 region of WT and VAChT KD HOM mice, which have 70% decrease in VAChT expression and similar deficit in ACh release (20,21). These mice present social memory deficits and also object recognition memory impairment (20,21).…”

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confidence: 99%

“…For these experiments, we recorded fEPSP in the CA1 region of WT and VAChT KD HOM mice, which have 70% decrease in VAChT expression and similar deficit in ACh release (20,21). These mice present social memory deficits and also object recognition memory impairment (20,21). We induced LTP in hippocampal slices using high frequency stimulation (100 Hz, 1 s) delivered to the Schaffercollaterals.…”

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confidence: 99%

“…Cholinergic tone has been associated with several memoryrelated functions (20,21), but depending on the approach and investigator, lesion of the medial septum cholinergic system caused varying degrees of spatial navigation impairment (11,12,16). Indeed, for some investigators cholinergic lesions did not cause impairment in spatial memory (15,23).…”

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confidence: 99%

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

Martyn¹,

Jaeger

Magalhães³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Basal forebrain cholinergic neurons, which innervate the hippocampus and cortex, have been implicated in many forms of cognitive function. Immunolesion-based methods in animal models have been widely used to study the role of acetylcholine (ACh) neurotransmission in these processes, with variable results. Cholinergic neurons have been shown to release both glutamate and ACh, making it difficult to deduce the specific contribution of each neurotransmitter on cognition when neurons are eliminated. Understanding the precise roles of ACh in learning and memory is critical because drugs that preserve ACh are used as treatment for cognitive deficits. It is therefore important to define which cholinergic-dependent behaviors could be improved pharmacologically. Here we investigate the contributions of forebrain ACh on hippocampal synaptic plasticity and cognitive behavior by selective elimination of the vesicular ACh transporter, which interferes with synaptic storage and release of ACh. We show that elimination of vesicular ACh transporter in the hippocampus results in deficits in long-term potentiation and causes selective deficits in spatial memory. Moreover, decreased cholinergic tone in the forebrain is linked to hyperactivity, without changes in anxiety or depression-related behavior. These data uncover the specific contribution of forebrain cholinergic tone for synaptic plasticity and behavior. Moreover, these experiments define specific cognitive functions that could be targeted by cholinergic replacement therapy.Alzheimer's disease | Morris water maze | synaptic vesicle | Barnes maze T he mechanisms that underlie the formation of hippocampaldependent spatial memory have been broadly explored (1). However, the neurochemical basis underlying changes in the strength of synaptic connections necessary for memories to persist is still not precisely understood. In the case of the hippocampus, mechanisms for memory processing include mRNA-dependent (2) and mammalian target of rapamycin (mTOR)-mediated protein synthesis (3) as well as a sequence of biochemical events shared with or closely similar to that of long-term potentiation (LTP) (2). Indeed, the consolidation of two different aversive tasks (4) and of spatial recognition memory (5) is accompanied by LTP of the CA3-CA1 synapse and can be occluded by a preceding LTP.The basal forebrain cholinergic system, which innervates the hippocampus and cortex, has been suggested to modulate LTP in the hippocampus (6-9) 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). Moreover, in few studies cholinergic denervation did not affect expression of LTP (13). Understanding the precise roles of ACh in learning and memory is of importance because in different types of dementia cholinergic function is decreased (14), and manipulations that boost ACh levels at synapses are used a...

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Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

Marchant,

Bryen,

Bahlo

et al. 2024

Ann Clin Transl Neurol

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ObjectiveMost families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence‐based recommendations for their integration into practice.MethodsIn total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research‐led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required.ResultsIntegration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice‐altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene‐panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today.InterpretationOur results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post‐exome auxiliary investigations extended our diagnostic yield by 81% overall (34–62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.

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Mice Deficient for the Vesicular Acetylcholine Transporter Are Myasthenic and Have Deficits in Object and Social Recognition

Cited by 215 publications

References 53 publications

Cholinergic filtering in the recurrent excitatory microcircuit of cortical layer 4

Cholinergic filtering in the recurrent excitatory microcircuit of cortical layer 4

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

Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

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