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Background and purpose:Central 5-HT-containing pathways are known to be important in cardiovascular regulation and a crucial area for this regulation is the nucleus tractus solitarius (NTS), which contains many of the known 5-HT receptor subtypes. In this study the role of 5-HT1B and 5-HT1D receptors, targets for the antimigraine drugs known collectively as triptans, was examined in the NTS.Experiment approach:Extracellular recordings were made, in anaesthetized rats, from 109 NTS neurones that were excited by electrical stimulation of the vagus and drugs were applied ionophoretically to these neurones.Key results:The 5-HT1B/1D receptor agonist sumatriptan applied to 64 neurones produced a 64% reduction in the firing rate of 54 of these neurones. Ketanserin, a 5-HT1D/2A receptor antagonist, alone had little effect, but co-applied with sumatriptan significantly attenuated this inhibition, whilst co-application of the 5-HT1B receptor antagonist GR55562 resulted in potentiation of this inhibition. Sumatriptan also caused a 25% reduction in vagal afferent evoked activity as well as that caused by stimulation of cardiopulmonary afferents. In another 41 neurones the 5-HT1B receptor agonist CP-93 129 produced a doubling of the background firing rate in 31 of these neurones and a significant increase in both vagal afferent evoked activity and that evoked by cardiopulmonary afferent activation.Conclusions and implications:Activation of 5-HT1B and 5-HT1D receptors have opposing actions on NTS neurones of excitation and inhibition, respectively. As both receptors are negatively coupled to adenylate cyclase this would indicate that they have different anatomical locations within NTS.British Journal of Pharmacology (2007) 150, 987–995. doi:10.1038/sj.bjp.0707169; published online 5 March 2007 [ABSTRACT FROM AUTHOR]

Intracellular accumulation of tau protein is a hallmark of Alzheimer's Disease and Progressive Supranuclear Palsy, as well as other neurodegenerative disorders collectively known as tauopathies. Despite our increasing understanding of the mechanisms leading to the initiation and progression of tau pathology, the field still lacks appropriate disease models to facilitate drug discovery. Here, we established a novel and modulatable seeding-based neuronal model of full-length 4R tau accumulation using humanized mouse cortical neurons and seeds from P301S human tau transgenic animals. The model shows specific and consistent formation of intraneuronal insoluble full-length 4R tau inclusions, which are positive for known markers of tau pathology (AT8, PHF-1, MC-1), and creates seeding competent tau. The formation of new inclusions can be prevented by treatment with tau siRNA, providing a robust internal control for use in qualifying the assessment of potential therapeutic candidates aimed at reducing the intracellular pool of tau. In addition, the experimental set up and data analysis techniques used provide consistent results in larger-scale designs that required multiple rounds of independent experiments, making this is a versatile and valuable cellular model for fundamental and early pre-clinical research of tau-targeted therapies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Amorim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In Alzheimer's disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models, we examined the relationship between these two processes and neuronal clearance. Accumulation of p62 (a marker of defective protein clearance) correlated with pathological tau accumulation in two mouse models of tauopathy spread; Entorhinal Cortex-tau (EC-Tau) mice where tau pathology progresses in time from EC to other brain regions, and PS19 mice injected with tau seeds. In both models and in several brain regions, p62 colocalized with human tau in a pathological conformation (MC1 antibody). In EC-Tau mice, p62 accumulated before overt tau pathology had developed and was associated with the presence of aggregation-competent tau seeds identified using a FRET-based assay. Furthermore, p62 accumulated in the cytoplasm of neurons in the dentate gyrus of EC-Tau mice prior to the appearance of MC1 positive tauopathy. However, MC1 positive tau was shown to be present at the synapse and to colocalize with p62 as shown by immuno electron microscopy. In vitro, p62 colocalized with tau inclusions in two primary cortical neuron models of tau pathology. In a three-chamber microfluidic device containing neurons overexpressing fluorescent tau, seeding of tau in the donor chamber led to tau pathology spread and p62 accumulation in both the donor and the recipient chamber. Overall, these data are in accordance with the hypothesis that the accumulation and trans-synaptic spread of pathological tau disrupts clearance mechanisms, preceding the appearance of obvious tau aggregation. A vicious cycle of tau accumulation and clearance deficit would be expected to feed-forward and exacerbate disease progression across neuronal circuits in human tauopathies., (© 2021. The Author(s).)

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with impaired motor function and several non-motor symptoms, with no available disease modifying treatment. Intracellular accumulation of pathological α-synuclein inclusions is a hallmark of idiopathic PD, whereas, dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial PD that is clinically indistinguishable from idiopathic PD. Recent evidence supports the hypothesis that an increase in LRRK2 kinase activity is associated with the development of not only familial LRRK2 PD, but also idiopathic PD. Previous reports have shown preclinical effects of LRRK2 modulation on α-synuclein-induced neuropathology. Increased subthalamic nucleus (STN) burst firing in preclinical neurotoxin models and PD patients is hypothesized to be causally involved in the development of the motor deficit in PD. To study a potential pathophysiological relationship between α-synuclein pathology and LRRK2 kinase activity in PD, we investigated the effect of chronic LRRK2 inhibition in an AAV-α-synuclein overexpression rat model. In this study, we report that chronic LRRK2 inhibition using PFE-360 only induced a marginal effect on motor function. In addition, the aberrant STN burst firing and associated neurodegenerative processes induced by α-synuclein overexpression model remained unaffected by chronic LRRK2 inhibition. Our findings do not strongly support LRRK2 inhibition for the treatment of PD. Therefore, the reported beneficial effects of LRRK2 inhibition in similar α-synuclein overexpression rodent models must be considered with prudence and additional studies are warranted in alternative α-synuclein-based models., (Copyright © 2019 Andersen et al.)

Agonists of the α 7 -nicotinic acetylcholine receptor (α 7 -nAChR) have entered clinical trials as procognitive agents for treating schizophrenia and Alzheimer's disease. The most advanced compounds are orthosteric agonists, which occupy the ligand binding site. At the molecular level, agonist activation of α 7 -nAChR is reasonably well understood. However, the consequences of activating α 7 -nAChRs on neural circuits underlying cognition remain elusive. Here we report that an α 7 -nAChR agonist (FRM-17848) enhances long-term potentiation (LTP) in rat septo-hippocampal slices far below the cellular EC 50 but at a concentration that coincides with multiple functional outcome measures as we reported in Stoiljkovic M, Leventhal L, Chen A, Chen T, Driscoll R, Flood D, Hodgdon H, Hurst R, Nagy D, Piser T, Tang C, Townsend M, Tu Z, Bertrand D, Koenig G, Hajós M. Biochem Pharmacol 97: 576-589, 2015. In this same concentration range, we observed a significant increase in spontaneous γ-aminobutyric acid (GABA) inhibitory postsynaptic currents and a moderate suppression of excitability in whole cell recordings from rat CA1 pyramidal neurons. This modulation of GABAergic activity is necessary for the LTP-enhancing effects of FRM-17848, since inhibiting GABA A α 5 -subunit-containing receptors fully reversed the effects of the α 7 -nAChR agonist. These data suggest that α 7 -nAChR agonists may increase synaptic plasticity in hippocampal slices, at least in part, through a circuit-level enhancement of a specific subtype of GABAergic receptor., (Copyright © 2016 the American Physiological Society.)

Background and Purpose: The 5-HT7 receptor is a GPCR that is the target of a broad range of antidepressant and antipsychotic drugs. Various studies have demonstrated an ability of the 5-HT7 receptor to modulate glutamatergic neurotransmission and cognitive processes although the potential impact upon AMPA receptors has not been investigated directly. The purposes of the present study were to investigate a direct modulation of the GluA1 AMPA receptor subunit and determine how this might influence AMPA receptor function., Experimental Approach: The influence of pharmacological manipulation of the 5-HT7 receptor system upon phosphorylation of GluA1 subunits was assessed by Western blotting of fractionated proteins from hippocampal neurones in culture (or proteins resident at the neurone surface) and the functional impact assessed by electrophysiological recordings in rat hippocampus in vitro and in vivo., Key Results: 5-HT7 receptor activation increased cAMP and relative pCREB levels in cultures of rat hippocampal neurones along with an increase in phosphorylation (Ser845) of the GluA1 AMPA receptor subunit evident in whole neurone extracts and within the neurone surface compartment. Electrophysiological recordings in rat hippocampus demonstrated a 5-HT7 receptor-mediated increase in AMPA receptor-mediated neurotransmission in vitro and in vivo., Conclusions and Implications: The 5-HT7 receptor-mediated phosphorylation of the GluA1 AMPA receptor provides a molecular mechanism consistent with the 5-HT7 receptor-mediated increase in AMPA receptor-mediated neurotransmission., (© 2016 The British Pharmacological Society.)

Prefibrillar assembly of amyloid-β (Aβ) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aβ synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aβ 1-42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aβ 1-42-induced aggregation and reduction in cell viability, respectively. In vivo long-term potentiation (LTP) determined effects on synaptic toxicity induced by intracerebroventricular (i.c.v.) injection of cell-derived Aβ oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aβ oligomers in normal rats. SEN1576 bound to monomeric Aβ 1-42, protected neuronal cells exposed to Aβ 1-42, reduced deficits in in vivo LTP and behaviour. SEN1576 exhibits the necessary features of a drug candidate for further development as a disease modifying treatment for the early stages of AD-like dementia.

It has been demonstrated previously that the vagal bradycardia evoked by activation of pulmonary C-fibres is not respiratory modulated. Experiments were carried out in alpha-chloralose anaesthetized cats to determine if these cardiac vagal preganglionic neurones (CVPNs) in the nucleus ambiguus (NA), which have respiratory modulated activity, can be activated when pulmonary C-fibre afferents are stimulated by right atrial injections of phenylbiguanide (PBG). Eleven CVPNs with B-fibre axons in the right cardiac vagal branches were identified and found to be localized within or ventrolateral to the nucleus ambiguus. Ionophoretic application of a high current of dl-homocysteic acid (DLH) induced a vagally mediated bradycardia and hypotension in six of eight sites from which CVPNs were recorded. The activity of B-fibre CVPNs, whether spontaneous (n = 4) or induced by ionophoresis of DLH (n = 7) was respiratory modulated, firing perferentially during post-inspiration and stage 2 expiration. This activity also correlated with the rising phase of the arterial blood pressure wave consistent with these CVPNs receiving an arterial baroreceptor input. Right atrial injections of PBG excited nine of eleven CVPNs tested. In eight of these activated neurones the onset latency of the excitation was within the pulmonary circulation time, consistent with being activated only by pulmonary C-fibre afferents. In two neurones the PBG-evoked excitation still occurred when central inspiratory drive was inhibited, as indicated by the disappearance of phrenic nerve activity. In conclusion, B-fibre respiratory modulated CVPNs can be activated following stimulation of pulmonary C-fibre afferents.