Biology subjects

Conn, P. J.

Publications and source records attributed to Conn, P. J..

7 recordsLinked to original sources

bioRxiv2024

Rostral Pedunculopontine Nucleus Infusion of M4 Positive Allosteric Modulator VU0467154 Augments L-DOPA Effects in Hemiparkinsonian Rats

Standard treatment for Parkinsons disease (PD) is dopamine replacement therapy with L-DOPA. However, chronic treatment often results in abnormal involuntary movements called L-DOPA-induced dyskinesia (LID). Prior evidence indicates that heightened striatal cholinergic tone may contribute to LID. Restoring cholinergic inhibition by targeting the inhibitory M4 muscarinic acetylcholine (ACh) receptor (M4) reduces LID in preclinical models. Although intrinsic striatal sources of ACh have been considered for their role in LID, extrinsic sources of ACh such as the pedunculopontine nucleus (PPN) have not been well investigated for their role in LID. Therefore, the current study employed hemiparkinsonian Long-Evans rats with a PPN-targeted cannula ipsilateral to 6-OHDA lesion. Following chronic treatment with L-DOPA, we examined the effect of local unilateral PPN infusion of M4 PAM VU0467154 on LID, motor performance, and c-fos expression within the PPN. It was expected that PPN infusion of VU0467154 would reduce LID, reduce L-DOPAs motor benefit, and globally reduce c-fos expression in the PPN. Contrary to our expectations, PPN infusion of M4 PAM did not significantly affect LID severity. Furthermore, the group receiving M4 PAM showed slightly elevated motor improvement compared to L-DOPA, and decreased c-fos expression specifically in PPN cholinergic neurons. These results suggest that local PPN ACh dynamics differ from those of the striatum. Specifically, our results suggest that PPN cholinergic neurons may be a promising therapeutic target for augmenting L-DOPA-mediated motor benefit without increasing LID.

neuroscience↗

bioRxiv2020

Ventral hippocampal mossy cell hyperactivity degrades dorsal hippocampal mnemonic function via longitudinal projections

BackgroundThe anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive, as is the ventral hippocampus in rodent models for schizophrenia risk. Hyperactive ventral hippocampal projections to extrahippocampal brain regions contribute to schizophrenia symptoms, but less is known about the functional effects of hyperactive projections within the hippocampal formation long axis. We approached this question by testing whether hyperactivation of ventral dentate gyrus (DG) mossy cells (MCs), which densely project intrahippocampally to the dorsal DG, influences spatial memory, a cognition dependent on intact dorsal DG function. MethodsIn CD-1 mice, we targeted dorsal DG-projecting ventral DG MCs using an adeno-associated virus intersectional strategy. In vivo fiber photometry recording of ventral DG MCs was performed during exploratory behaviors. We targeted excitatory chemogenetic constructs to ventral DG MCs and tested whether their hyperactivation impaired encoding in a spatial memory task. ResultsVentral DG MCs were activated during behavior related to environmental information gathering (rearing) but not during non-exploratory motor behaviors. Ventral DG MCs made functional monosynaptic inputs to dorsal DG granule cells, with chemogenetic activation of ventral DG MCs leading to increased activity of dorsal DG granule cells. Finally, chemogenetic activation of ventral DG MCs during the encoding phase of an object location memory task impaired retrieval 24 hours later, without effects on locomotion or other exploratory behaviors. ConclusionsThese data suggest that localized hippocampal hyperactivity may have longitudinal intrahippocampal functional consequences, supporting study of longitudinal circuits as targets to mitigate cognitive deficits associated with schizophrenia.

neuroscience↗

bioRxiv2020

Activating mGlu3 metabotropic glutamate receptors rescues schizophrenia-like cognitive deficits through metaplastic adaptations within the hippocampus.

BackgroundPolymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu3 receptors regulate synaptic plasticity and cognition. MethodsWe examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu3 receptor expression in specific neuronal subpopulations. ResultsmGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through a mGlu5 receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function. ConclusionsThese data demonstrate that activation of mGlu3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function - providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.

pharmacology and toxicology↗

bioRxiv2020

Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo anti-parkinsonian and anti-dystonic efficacy

Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M4 receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.

pharmacology and toxicology↗

bioRxiv2020

Contrasting adaptations to synaptic physiology of prefrontal cortex interneuron subtypes in a mouse model of binge drinking

Alcohol use disorder (AUD) affects all sexes, however women who develop AUD may be particularly susceptible to cravings and other components of the disease. While many brain regions are involved in AUD etiology, proper function of the prefrontal cortex (PFC) is particularly important for top-down craving management and the moderation of drinking behaviors. Essential regulation of PFC output is provided by local inhibitory interneurons, yet the effects of chronic drinking on interneuron physiology remain poorly understood, particularly in female individuals. To address this gap, we generated fluorescent reporter transgenic mice to label the two major classes of interneuron in deep layer prelimbic PFC, based on expression of parvalbumin (PV-IN) or somatostatin (SST-IN). We then interrogated PV-IN and SST-IN membrane and synaptic physiology in a rodent model of binge drinking. Beginning in late adolescence, mice received 3-4 weeks of intermittent access (IA) ethanol. One day after the last drinking session, adaptations to PV-IN and SST-IN intrinsic physiology were observed in male mice but not in female mice. Furthermore, IA ethanol precipitated diametrically opposing changes to PV-IN synaptic physiology based on sex. IA ethanol decreased excitatory synaptic strength onto PV-INs from female mice and potentiated excitatory transmission onto PV-INs male mice. In contrast, decreased synaptic strength onto SST-INs was observed following IA ethanol in all groups of mice. Together, these findings illustrate novel sex differences in drinking-related PFC pathophysiology. Discovering means to restore PV-IN and SST-IN dysfunction following extended drinking provides opportunities for developing new treatments for all AUD patients.

neuroscience↗

bioRxiv2019

Biased M1 positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

Highly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for the potential improvement of cognitive function in patients suffering from Alzheimers disease and schizophrenia. M1 PAM discovery programs have produced a structurally diverse range of M1 PAMs with distinct pharmacological properties, including different levels of agonist activity and differences in signal bias. This includes the recent discovery of novel biased M1 PAMs that can potentiate coupling of M1 to activation of phospholipase C but not phospholipase D (PLD). However, little is known about the role of PLD in M1 signaling in native systems and it is not clear whether biased M1 PAMs will display differences in modulating M1-mediated responses in native tissue. We now report a series of studies using novel PLD inhibitors and PLD knockout mice to show that PLD is necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Importantly, biased M1 PAMs that do not couple to PLD not only fail to potentiate orthosteric agonist-induced LTD but also block M1-dependent LTD in the PFC. In contrast, biased and non-biased M1 PAMs act similarly in potentiating M1-dependent electrophysiological responses that are PLD-independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain CNS functions and that biased M1 PAMs function differently in brain regions implicated in cognition.\n\nSummaryWe demonstrate a novel role of phospholipase D in M1-dependent rodent cortical plasticity and M1 PAMs that do not couple to phospholipase D have functionally distinct effects on cortical plasticity than non-biased M1 PAMs.

neuroscience↗

bioRxiv2019

Positive allosteric modulation of metabotropic glutamate receptor 5 modulates Akt and GSK3β signaling in vivo

BackgroundPositive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) have behavioral effects predictive of antipsychotic activity in experimental models such as amphetamine-induced hyperlocomotion (AHL). However, the signaling mechanisms that contribute to the antipsychotic-like properties of mGlu5 PAMs are not well understood.\n\nMethodsBecause the Akt/GSK3{beta} pathway has been implicated in schizophrenia and is modulated by known antipsychotic drugs, we evaluated the effects of systemic administration of two mGlu5 PAMs on Akt and GSK3{beta} signaling using western blot analysis in both naive and amphetamine-treated adult male rats.\n\nResultsIn the dorsal striatum, the mGlu5-selective PAM VU0092273 (30 mg/kg) significantly increased Akt phosphorylation at residues associated with enhanced kinase activity, Thr308 and Ser473. Inhibitory phosphorylation of GSK3{beta} at Ser9 was also increased. Similar effects were observed with a second mGlu5 PAM, VU0360172 (56.6 mg/kg). VU0092273 increased Akt phosphorylation levels in amphetamine-treated rats. Effects on Akt/GSK3{beta} signaling were not limited to the striatum, as VU0092273 also increased Akt/GSK3{beta} phosphorylation in the medial prefrontal cortex.\n\nConclusionsThese findings suggest that mGlu5 PAMs that have antipsychotic-like efficacy in rats affect signaling pathways that are modulated by known antipsychotics, and raise the possibility that inhibition of GSK3{beta} might contribute to the antipsychotic-like effects of mGlu5 PAMs.

neuroscience↗