Diverse glutamatergic inputs target spines expressing M1 muscarinic receptors in the basolateral amygdala: An ultrastructural analysis

McDonald, Alexander J.; Jones, Grace C.; Mott, David D.

doi:10.1016/j.brainres.2019.146349

Cited by 7 publications

(5 citation statements)

References 52 publications

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“…Interestingly, the glutamatergic pyramidal neurons account for ∼90% of hippocampal neurons, a much higher percentage than in other parts of the cortex, supporting our observations of dark neuron frequencies in the hippocampus ( Olbrich and Braak, 1985 ). Further support for this hypothesis comes from the observation that ACh can modulate glutamatergic inputs to pyramidal neurons in the amygdala by presynaptic as well as postsynaptic Chrm1-mediated mechanisms ( McDonald et al, 2019 ). On the other hand, Chrm4, a paralog of Chrm1, mediates the cholinergic inhibition of glutamatergic response in corticostriatal neurons ( Pancani et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal versus cortical deletion of cholinergic receptor muscarinic 1 in mice differentially affects post-translational modifications and supramolecular assembly of respiratory chain-associated proteins, mitochondrial ultrastructure, and respiration: implications in Alzheimer’s disease

Sabbir

Swanson

Speth

et al. 2023

Front. Cell Dev. Biol.

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Introduction: In a previous retrospective study using postmortem human brain tissues, we demonstrated that loss of Cholinergic Receptor Muscarinic 1 (CHRM1) in the temporal cortex of a subset of Alzheimer’s patients was associated with poor survival, whereas similar loss in the hippocampus showed no such association. Mitochondrial dysfunction underlies Alzheimer’s pathogenesis. Therefore, to investigate the mechanistic basis of our findings, we evaluated cortical mitochondrial phenotypes in Chrm1 knockout (Chrm1−/−) mice. Cortical Chrm1 loss resulted in reduced respiration, reduced supramolecular assembly of respiratory protein complexes, and caused mitochondrial ultrastructural abnormalities. These mouse-based findings mechanistically linked cortical CHRM1 loss with poor survival of Alzheimer’s patients. However, evaluation of the effect of Chrm1 loss on mouse hippocampal mitochondrial characteristics is necessary to fully understand our retrospective human tissue-based observations. This is the objective of this study.Methods: Enriched hippocampal and cortical mitochondrial fractions (EHMFs/ECMFs, respectively) derived from wild-type and Chrm1−/− mice were used to measure respiration by quantifying real-time oxygen consumption, supramolecular assembly of oxidative phosphorylation (OXPHOS)-associated proteins by blue native polyacrylamide gel electrophoresis, post-translational modifications (PTMs) by isoelectric focusing (IEF), and mitochondrial ultrastructure by electron microscopy.Results: In contrast to our previous observations in Chrm1−/− ECMFs, EHMFs of Chrm1−/− mice significantly increased respiration with a concomitant increase in the supramolecular assembly of OXPHOS-associated proteins, specifically Atp5a and Uqcrc2, with no mitochondrial ultrastructural alterations. IEF of ECMFs and EHMFs from Chrm1−/− mice showed a decrease and an increase, respectively in a negatively charged (pH∼3) fraction of Atp5a relative to the wild-type mice, with a corresponding decrease or increase in the supramolecular assembly of Atp5a and respiration indicating a tissue-specific signaling effect.Discussion: Our findings indicate that loss of Chrm1 in the cortex causes structural, and physiological alterations to mitochondria that compromise neuronal function, whereas Chrm1 loss in the hippocampus may benefit neuronal function by enhancing mitochondrial function. This brain region-specific differential effect of Chrm1 deletion on mitochondrial function supports our human brain region-based findings and Chrm1−/− mouse behavioral phenotypes. Furthermore, our study indicates that Chrm1-mediated brain region-specific differential PTMs of Atp5a may alter complex-V supramolecular assembly which in turn regulates mitochondrial structure-function.

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Section: Discussionmentioning

confidence: 99%

Hippocampal versus cortical deletion of cholinergic receptor muscarinic 1 in mice differentially affects post-translational modifications and supramolecular assembly of respiratory chain-associated proteins, mitochondrial ultrastructure, and respiration: implications in Alzheimer’s disease

Sabbir

Swanson

Speth

et al. 2023

Front. Cell Dev. Biol.

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“…Some of the m1R+ structures appeared to be dendrites, but structures contributing to the more diffuse neuropilar immunoreactivity will require ultrastructural analysis to be resolved. Electron microscopic studies of the rodent BNC have shown that dendritic shafts and dendritic spines of PNs express m1Rs (McDonald et al, 2019; Muller et al, 2013). These structures are also the main postsynaptic targets of cholinergic inputs to the BNC from the basal forebrain (Carlsen & Heimer, 1986; Muller et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…These structures are also the main postsynaptic targets of cholinergic inputs to the BNC from the basal forebrain (Carlsen & Heimer, 1986; Muller et al, 2011). In addition, axon terminals forming asymmetrical (excitatory) synapses or symmetrical (inhibitory or modulatory) synapses are m1R+ in rodents (asymmetrical: 90%; symmetrical: 10%) (McDonald et al, 2019; Muller et al, 2013). Although axon terminals of BNC PNs form asymmetrical (excitatory) synapses, these synapses are also formed by glutamatergic inputs from the cortex and thalamus (Amir et al, 2019; Brinley‐Reed et al, 1995; LeDoux et al, 1991; McDonald et al, 2019; Smith et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Neuronal localization of m1 muscarinic receptor immunoreactivity in the monkey basolateral amygdala

McDonald

Mott

2021

J Comp Neurol

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The basolateral nuclear complex (BNC) of the amygdala plays an important role in the generation of emotional/motivational behavior and the consolidation of emotional memories. Activation of M1 cholinergic receptors (M1Rs) in the BNC is critical for memory consolidation. Previous receptor binding studies in the monkey amygdala demonstrated that the BNC has a high density of M1Rs, but did not have sufficient resolution to identify which neurons in the BNC expressed them. This was accomplished in the present immunohistochemical investigation using an antibody for the m1 receptor (m1R). Analysis of m1Rs in the monkey BNC using immunoperoxidase techniques revealed that their expression was very dense in the BNC, and suggested that virtually all of the pyramidal projection neurons (PNs) in all of the BNC nuclei were m1R‐immunoreactive (m1R+). This was confirmed with dual‐labeling immunofluorescence using staining for calcium/calmodulin‐dependent protein kinase II (CaMK) as a marker for BNC PNs. However, additional dual‐labeling studies indicated that one‐third of inhibitory interneurons (INs) expressing glutamic acid decarboxylase (GAD) were also m1R+. Moreover, the finding that 60% of parvalbumin (PV) immunoreactive neurons were m1R+ indicated that this IN subpopulation was the main GAD+ subpopulation exhibiting m1R expression. The cholinergic innervation of the amygdala is greatly reduced in Alzheimer's disease and there is currently considerable interest in developing selective M1R positive allosteric modulators (PAMs) to treat the symptoms. The results of the present study indicate that M1Rs in both PNs and INs in the primate BNC would be targeted by M1R PAMs.

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“…These inputs are complementary, with VGluT1+ inputs arising mainly from cortical structures and the BNC, and VGluT2+ inputs arising mainly from subcortical structures, such as the midline thalamus (Fremeau Jr. et al., 2001; Kaneko & Fujiyama, 2002). It was found that about half of the spines that are postsynaptic to VGluT1+ or VGluT2+ terminals in the BLa are M1R+ (McDonald et al., 2019) (Figure 8a–d). These results indicate that both cortical/BNC and thalamic inputs to BLa spines could be modulated by postsynaptic M1Rs that potentiate NMDAR currents.…”

Section: Localization Of Muscarinic Cholinergic Receptors In the Bncmentioning

confidence: 99%

“…The colocalization of M1Rs and NMDARs in these spines suggests that excitatory inputs to the BLa PNs, which mainly arise in cortical areas, midline thalamic nuclei, or BNC PNs, may terminate on M1R+ spines. A dual‐labeling EM study used antibodies to two different vesicular glutamate transporter proteins (VGluTs) to label two different sets of glutamatergic inputs to M1R+ spines (McDonald et al., 2019). These inputs are complementary, with VGluT1+ inputs arising mainly from cortical structures and the BNC, and VGluT2+ inputs arising mainly from subcortical structures, such as the midline thalamus (Fremeau Jr. et al., 2001; Kaneko & Fujiyama, 2002).…”

Section: Localization Of Muscarinic Cholinergic Receptors In the Bncmentioning

confidence: 99%

Functional neuroanatomy of basal forebrain projections to the basolateral amygdala: Transmitters, receptors, and neuronal subpopulations

McDonald

2024

J of Neuroscience Research

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The projections of the basal forebrain (BF) to the hippocampus and neocortex have been extensively studied and shown to be important for higher cognitive functions, including attention, learning, and memory. Much less is known about the BF projections to the basolateral nuclear complex of the amygdala (BNC), although the cholinergic innervation of this region by the BF is actually far more robust than that of cortical areas. This review will focus on light and electron microscopic tract‐tracing and immunohistochemical (IHC) studies, many of which were published in the last decade, that have analyzed the relationship of BF inputs and their receptors to specific neuronal subtypes in the BNC in order to better understand the anatomical substrates of BF‐BNC circuitry. The results indicate that BF inputs to the BNC mainly target the basolateral nucleus of the BNC (BL) and arise from cholinergic, GABAergic, and perhaps glutamatergic BF neurons. Cholinergic inputs mainly target dendrites and spines of pyramidal neurons (PNs) that express muscarinic receptors (MRs). MRs are also expressed by cholinergic axons, as well as cortical and thalamic axons that synapse with PN dendrites and spines. BF GABAergic axons to the BL also express MRs and mainly target BL interneurons that contain parvalbumin. It is suggested that BF‐BL circuitry could be very important for generating rhythmic oscillations known to be critical for emotional learning. BF cholinergic inputs to the BNC might also contribute to memory formation by activating M1 receptors located on PN dendritic shafts and spines that also express NMDA receptors.

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Diverse glutamatergic inputs target spines expressing M1 muscarinic receptors in the basolateral amygdala: An ultrastructural analysis

Cited by 7 publications

References 52 publications

Hippocampal versus cortical deletion of cholinergic receptor muscarinic 1 in mice differentially affects post-translational modifications and supramolecular assembly of respiratory chain-associated proteins, mitochondrial ultrastructure, and respiration: implications in Alzheimer’s disease

Hippocampal versus cortical deletion of cholinergic receptor muscarinic 1 in mice differentially affects post-translational modifications and supramolecular assembly of respiratory chain-associated proteins, mitochondrial ultrastructure, and respiration: implications in Alzheimer’s disease

Neuronal localization of m1 muscarinic receptor immunoreactivity in the monkey basolateral amygdala

Functional neuroanatomy of basal forebrain projections to the basolateral amygdala: Transmitters, receptors, and neuronal subpopulations

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