Biology subjects

Suryavanshi, P.

Publications and source records attributed to Suryavanshi, P..

3 recordsLinked to original sources

bioRxiv2023

Brief excitotoxic insults cause a calpain-mediated increase in nuclear membrane permeability in neonatal neurons.

Neuronal swelling after excitotoxic insults is implicated in neuronal injury and death in the developing brain, yet mitigating brain edema with osmotic and surgical interventions yields poor clinical outcomes. Importantly, neuronal swelling and its downstream consequences during early brain development remain poorly investigated. Using multiphoton Ca2+ imaging in vivo (P12-17) and in acute brain slices (P8-12), we explored Ca2+-dependent downstream effects after neuronal cytotoxic edema. We observed the translocation of cytosolic GCaMP6s into the nucleus of a subpopulation of neurons minutes after various excitotoxic insults. We used automated morphology-detection algorithms for neuronal segmentation and quantified the nuclear translocation of GCaMP6s as the ratio of nuclear and cytosolic intensity (N/C ratio). Elevated neuronal N/C ratios were correlated to higher Ca2+ loads and could occur independently of neuronal swelling. Electron microscopy revealed that the nuclear translocation was associated with increased nuclear pore size. Inhibiting calpains prevented elevated N/C ratios and neuronal swelling. Thus, our results indicate altered nuclear transport in a subpopulation of neurons shortly after injury in the developing brain, which can be used as an early biomarker of acute neuronal injury.

neuroscience↗

bioRxiv2020

Non-canonical glutamate signaling in a genetic model of migraine with aura

Migraine with aura is an extremely common but poorly understood sensory circuit disorder. Monogenic models allow an opportunity to understand its mechanisms, in particular because the migraine aura is associated with spreading depolarizations that can be measured physiologically. Using fluorescent glutamate imaging in awake mice carrying a familial hemiplegic migraine type 2 mutation, we recorded previously undescribed spontaneous plumes of glutamate signaling that anatomically overlapped with reduced density of GLT-1a positive astrocyte processes. These events could be mimicked in wild-type animals by inhibition of glutamate clearance, which we show to be slower during sensory processing in FHM2 carriers. Plumes depended on calcium mediated vesicular release from neurons, but not action potentials. Importantly, a rise in both basal glutamate and plume frequency predicted the onset of spreading depolarization in WT and FHM2 animals, providing a novel mechanism in migraine with aura and by extension the many other neurological disorders where spreading depolarizations occur.

neuroscience↗

bioRxiv2019

Altered synaptic adaptation and gain in sensory circuits of the casein kinase 1 delta (CK1dT44A) mouse model of migraine

Migraine is a common and disabling neurological disorder. The headache and sensory amplifications that characterize migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. This is partly due to the paucity of genetic animal models associated with the common, less severe form of the disease. A mutation in casein kinase 1 delta (CK1{delta}) was identified in familial migraine with aura and advanced sleep phase syndrome. Spreading depolarization (SD), the phenomenon that underlies migraine aura, is facilitated in mice carrying one of the mutations (CK1{delta}T44A). However, the mechanism of this susceptibility is not known. We used a combination of whole-cell electrophysiology and imaging, in vivo and in ex vivo brain slices, to understand the cellular and synaptic underpinnings of this apparent circuit excitability. We found that despite normal synaptic activity and hyperpolarized neuronal membrane potentials at rest, CK1{delta}T44A neurons were more excitable upon repetitive stimulation compared to wild-type (WT) controls. This was due to reduced presynaptic adaptation to high-frequency stimuli at excitatory, but not inhibitory synapses. Reduced adaptation at glutamatergic CK1{delta}T44A synapses was mediated by a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles. This caused an increase in the cumulative amplitude of excitatory currents, and a higher excitation-to-inhibition ratio during sustained activity, both in vivo and in brain slices. Fluorescence imaging revealed increased glutamate release in CK1{delta}T44A compared to WT brain slices, corroborating the presynaptic gain of function observed with electrophysiology. Action potential bursts elicited in individual CK1{delta}T44A neurons enhanced glutamatergic feedback excitation within local microcircuits, further amplifying firing frequencies. At a network level in vivo, CK1{delta}T44A mice showed increased duration of up state activity, which is dependent on recurrent excitation. Finally, we demonstrated that SD susceptibility of CK1{delta}T44A brain slices could be returned to WT levels with the same reductions in extracellular calcium that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased SD susceptibility and may also explain the sensory amplifications that are associated with the disease.

neuroscience↗