Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps

Sajadi, Ahmadali; Provost, Chloé; Pham, Brendon; Brouillette, Jonathan

doi:10.3791/54215

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…Surgical procedure and injections. The cannula implantation surgery was adapted from the procedure previously described 12,47 . Briefly, mice were anesthetized with Ketamine/Xylazine (120/10 mg/kg), installed on a stereotaxic apparatus and maintained under anesthesia using 1% isoflurane.…”

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confidence: 99%

“…The injections were conducted as previously described 12,47 . In brief, one week after recovery, freely moving mice were injected with Aβ solutions or an equal volume of control AβScr or vehicle (VH: 50 mm Tris, 1 mm EDTA, pH 7.5) at a constant rate of 0.2 μl/min via cannulas and PE50 tubing (Plastics One) connected to a Hamilton syringe pump system (KD Scientific, KDS310).…”

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confidence: 99%

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Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

Dufort-Gervais

Provost

Charbonneau

et al. 2020

Sci Rep

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Synapse loss occurs early and correlates with cognitive decline in Alzheimer's disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aβo), but the exact synaptic components targeted by Aβo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aβo, and that it can modulate Aβo toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal Aβo injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal Aβo injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that Aβo contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during Aβo-driven neurodegeneration. Synapse loss is an early event in the pathogenesis of Alzheimer's disease (AD) and correlates with cognitive decline of the patients 1-3. Hippocampus-dependent memory for recent facts and events (explicit memory) is among the first type of memory that is affected in the disease because of the neurodegenerative process that rapidly and gradually takes place in the hippocampus at the onset of AD 4,5. More precisely, within the hippocampal network, the perforant path that connects the entorhinal cortex to the dentate gyrus (DG) is one of the earliest and most severely affected pathways in AD 6,7. This suggests that the DG is among sites showing initial signs of synaptic dysfunction, including in glutamatergic transmission 8 , and that it could represent an area of particular relevance for early interventions. Despite decades of research focused on the amyloid-beta (Aβ) peptide, its causal role in AD pathogenesis remains unclear at the molecular level. However, strong evidence suggests that soluble Aβ oligomers (Aβo) are particularly neurotoxic and that their presence can correlate with memory deficits in AD patients and animal models, especially when considering oligomers derived from Aβ 1-42 peptides 9-18. Soluble Aβo start to accumulate in the human brain ~10 to 15 years before clinical symptoms and were shown to induce losses of excitatory synapses and neurons 19-22. The oligomerization of Aβ is rapid and it has been suggested that Aβ toxicity results

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confidence: 99%

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confidence: 99%

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

Dufort-Gervais

Provost

Charbonneau

et al. 2020

Sci Rep

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“…Mice received osmotic pump installation on the 7 th day post-PT surgery. Osmotic pumps were filled with MDL 100907 (2.5 mM, 180 µL, Tocris) and kept in sterile distilled water at 37°C overnight before installation [11]. In stroked mice, an incision between the shoulder blades was made and an osmotic pump was connected to the free end of the PE50 catheter, which was left in the pocket in advance.…”

Section: Methodsmentioning

confidence: 99%

The Neuronal Activation of Deep Cerebellar Nuclei Is Essential for Environmental Enrichment-Induced Post-Stroke Motor Recovery

Zhang¹,

Wu²,

Shi³

et al. 2019

Aging and disease

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The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. We reasoned that the cerebellum may be an important player in post-stroke rehabilitation. Because the neurons in the deep cerebellar nuclei (DCN) represent virtually all of the output from the cerebellum, in this study, using environmental enrichment (EE) to promote rehabilitation, we investigated the influence of the optogenetic neuronal modulation of DCN on EE-induced rehabilitation. We found that neuronal inhibition of the DCN almost completely blocked motor recovery in EE treated mice, but the stroke mice with neuronal activation of the DCN achieved a similar recovery level as those in the EE treated group. No difference was observed in anxiety-like behavior. Moreover, Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq. This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. We further verified this using the 5-HT2A receptor antagonist, MDL100907, to inhibit the function of 5-HT2A receptor in the DCN. This treatment resulted in impaired recovery in EE treated mice, who performed at a level as poor as the stroke-only group. Thus, this work contributes to an understanding of the importance of the DCN activation in EE-induced post-stroke rehabilitation. Attempts to clarify the mechanism of 5-HT2A receptor-mediated signaling in the DCN may also lead to the creation of a pharmacological mimetic of the benefits of EE-induced rehabilitation.

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“…Drug microinjection protocols were adapted from previously published studies (Sajadi et al, 2016). Mice were habituated to handling and manipulation of the dummy cannula for 3 consecutive days prior to behavioral testing.…”

Section: Drug Microinjection Proceduresmentioning

confidence: 99%

Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

Brockway

Moyer

Aloimonos

et al. 2022

Preprint

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BackgroundSomatostatin (SST) neurons in the prelimbic (PL) cortex mediate a variety of behavioral states, ranging from alcohol consumption to fear learning and avoidance-related behaviors. However, little is known about the role of somatostatin peptide signaling itself to cortical functioning and behavior. Here, we sought to characterize the unique physiological and behavioral roles of the SST peptide in the PL cortex.MethodsWe employed a combination of ex vivo electrophysiology, in vivo calcium monitoring, and in vivo peptide pharmacology to explore the role of SST neuron and peptide signaling in the mouse PL cortex. Whole-cell slice electrophysiology was conducted in C57BL/6J male and female mice in pyramidal and GABAergic neurons of the PL cortex to characterize the pharmacological mechanism of SST signaling. Fiber photometry recordings of GCaMP6f fluorescent calcium signals from SST neurons were conducted to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field (OF). We further used local delivery of a broad SST receptor (SSTR) agonist into bilateral PL cortex to test causal effects of SST signaling on these same exploratory behaviors.ResultsSSTR activation broadly hyperpolarized layer 2/3 pyramidal neurons in the PL cortex in both male and female mice ex vivo, through both monosynaptic and polysynaptic GABA neuron-mediated mechanisms of action. This hyperpolarization was blocked by pre-application of the SSTR antagonist cyclo-somatostatin (cyclo-SST) and was non-reversible. SST neurons in PL were activated during EPM and OF exploration, indicating task-related recruitment of these neurons. Lastly, in line with this exploration-related activity profile, SSTR agonist administration directly into the PL enhanced open arm exploration in the EPM.ConclusionsHere we reveal a novel role for the SST peptide system within the PL cortex, by demonstrating a peptide-induced hypoexcitability of PL circuits and modulation of PL-dependent exploratory behaviors.

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Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps

Cited by 6 publications

References 34 publications

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

The Neuronal Activation of Deep Cerebellar Nuclei Is Essential for Environmental Enrichment-Induced Post-Stroke Motor Recovery

Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

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