Cytosolic PSD-95 interactor alters functional organization of neural circuits and AMPA receptor signaling independent of PSD-95 binding

Rodriguez, Ana R.; Anderson, Erin D.; O’Neill, Karen; McEwan, Przemyslaw Peter; Vigilante, Nicholas; Kwon, Munjin; Akum, Barbara F.; Stawicki, Tamara M.; Meaney, David F.; Firestein, Bonnie L.

doi:10.1162/netn_a_00173

Cited by 6 publications

(18 citation statements)

References 75 publications

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“…Furthermore, mechanical hyperalgesia occurs as a result of AMPA receptor and mGlu receptor coactivation and downstream signaling. In line with this, overexpression of cypin results in changes to AMPA receptor signaling ( Rodriguez et al, 2021 ), and inhibition of cypin by B9 may act to block AMPA receptor signaling responsible for mediating mechanical hyperalgesia.…”

Section: Discussionmentioning

confidence: 89%

Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury–Induced Mechanical Pain

Singh,

Gandu,

et al. 2024

eNeuro

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Cypin (cytosolicpostsynaptic density protein 95interactor) is the primary guanine deaminase (GDA) in the central nervous system (CNS), promoting the metabolism of guanine to xanthine, an important reaction in the purine salvage pathway. Activation of the purine salvage pathway leads to the production of uric acid (UA). UA has paradoxical effects, specifically in the context of CNS injury as it confers neuroprotection, but it also promotes pain. Since neuropathic pain is a comorbidity associated with spinal cord injury (SCI), we postulated that small molecule cypin inhibitor B9 treatment could attenuate SCI-induced neuropathic pain, potentially by interfering with UA production. However, we also considered that this treatment could hinder the neuroprotective effects of UA, and in doing so, exacerbate SCI outcomes. To address our hypothesis, we induced a moderate mid-thoracic contusion SCI in female mice and assessed whether transient intrathecal administration of B9, starting at 1 day post injury (pi) until 7 days pi, attenuates mechanical pain in hindlimbs at 3 weeks pi. We also evaluated the effects of B9 on the spontaneous recovery of locomotor function. We found that B9 alleviates mechanical pain but does not affect locomotor function. Importantly, B9 does not exacerbate lesion volume at the epicenter. In accordance with these findings, B9 does not aggravate glutamate-induced excitotoxic death of SC neuronsin vitro. Moreover, SCI-induced increased astrocyte reactivity at the glial scar is not altered by B9 treatment. Our data suggest that B9 treatment reduces mechanical pain without exerting major detrimental effects following SCI.Statement of SignificanceNeuropathic pain is a debilitating comorbidity associated with spinal cord injury (SCI). Available pharmacological therapies are ineffective or have adverse effects. Development of new and targeted drugs that can effectively alleviate neuropathic pain is urgently needed. Cypin is the primary guanine deaminase in the central nervous system and an essential enzyme in the purine salvage pathway. Activation of the purine salvage pathway leads to production of uric acid, which promotes pain, but also, neuroprotection. We found that inhibition of cypin post-SCI alleviates mechanical pain. The inhibitor does not prevent the spontaneous recovery of locomotor function or exacerbate lesion volume and astrogliosis at the injury epicenter. Thus, cypin inhibitors could be promising therapies for the treatment of neuropathic pain.

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Section: Discussionmentioning

confidence: 89%

Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury–Induced Mechanical Pain

Singh,

Gandu,

et al. 2024

eNeuro

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“…2c ). We calculate local efficiency as previously reported 17 , where we use cross-correlation of binned spiking activity to generate functional connectivity matrices (Fig. 2d ); representative matrices are shown for the control condition at all timepoints.…”

Section: Resultsmentioning

confidence: 99%

“…9a ) based on the work of Masquelier and Deco 41 . In particular, we modified and extended their model and our previous work 17 to better match the specific characteristics of our in vitro neuronal cultures, including neuronal E/I balance (Fig. 5d, e ), synaptic E/I balance (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…9c ). Our groups previously showed that, despite this “burstiness,” the network model can be tailored to successfully match activity metrics, such as burstlet rate and local efficiency, but less faithfully reproduces metrics that measure subtle variation in firing across electrodes, such as Fano factor 17 . Despite this limitation, our model captures the important overall effects of BDNF and glutamate application.…”

Section: Discussionmentioning

confidence: 99%

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Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry

O’Neill,

Anderson,

Mukherjee

et al. 2023

Commun Biol

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Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture. Importantly, these effects are not obvious when traditional activity metrics are used, so we delve more deeply into network organization, functional analyses, and in silico simulations. We demonstrate that BDNF partially restores homeostasis by promoting recovery of weak and medium connections after injury. Imaging and computational analyses suggest these effects are caused by changes to inhibitory neurons and connections. From our in silico simulations, we find that BDNF remodels the network by indirectly strengthening weak excitatory synapses after injury. Ultimately, our findings may explain the difficulties encountered in preclinical and clinical trials with BDNF and also offer information for future trials to consider.

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“…For co-culture experiments, astrocytes were prepared as described above. At one to two weeks after the astrocyte dissection, neurons were prepared as previously described from rats at embryonic day of gestation 18 (E18) [126][127][128][129][130][131]. Briefly, embryos were removed via Caesarian section and decapitated.…”

Section: Rat Cortical Astrocyte Culture Preparation Maintenance Plati...mentioning

confidence: 99%

Decoding natural astrocyte rhythms: dynamic actin waves result from environmental sensing by primary rodent astrocytes

O’Neill

Saracino

Barile

et al. 2021

Preprint

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Astrocytes are key regulators of brain homeostasis, which is essential for proper cognitive function. The role of cytoskeletal dynamics in this critical regulatory process is unknown. Here we find that actin is dynamic in certain subcellular regions, especially near the cell boundary. Our results further indicate that actin dynamics concentrates into hotspot regions that selectively respond to certain chemophysical stimuli, specifically the homeostatic challenges of ion or water concentration increases. Substrate topography makes actin dynamics more frequent yet weaker, and it also alters actin network structure. Superresolution images analyzed with a filament extraction algorithm demonstrate that surface topography is associated with a predominant perpendicular alignment of actin filaments near the cell boundary whereas flat substrates result in an actin cortex mainly parallel to the cell boundary. Thus, actin structure and dynamics together integrate information from different aspects of the environment that might steer the operation of neural cell networks.

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Cytosolic PSD-95 interactor alters functional organization of neural circuits and AMPA receptor signaling independent of PSD-95 binding

Cited by 6 publications

References 75 publications

Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury–Induced Mechanical Pain

Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury–Induced Mechanical Pain

Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry

Decoding natural astrocyte rhythms: dynamic actin waves result from environmental sensing by primary rodent astrocytes

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