Biology subjects

Teskey, G. C.

Publications and source records attributed to Teskey, G. C..

8 recordsLinked to original sources

bioRxiv2026

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗

bioRxiv2024

A Markovian neural barcode representing mesoscale cortical spatiotemporal dynamics.

Mesoscale cortical dynamics consist of stereotyped patterns of recurring activity motifs, however the constraints and rules governing how these motifs assemble over time is not known. Here we propose a Continuous Time Markov Chain model that probabilistically describes the temporal sequence of activity motifs using Markov Elements derived using semi-binary non-negative matrix factorization. Although derived from a discovery sample, these can be applied to new recordings from new mice. Unwrapping the associated transition probability matrix creates a Markovian neural barcode describing the probability of Markov element transitions as a compact and interpretable representation of neocortical dynamics. We show broad utility across a range of common mesoscale cortical imaging applications, ranging from time-locked events to pathological models. Moreover, it allows the discovery of new and emergent Markov Elements that unmask the flexibility of constraints governing cortical dynamics. The Markovian neural barcode provides a novel and powerful tool to characterize cortical function.

neuroscience↗

bioRxiv2023

Unilateral hippocampal stroke in freely behaving mice reveals sex differences in contralesional spreading depolarization and associated behavior

Ischemic stroke, brain tissue infarction following obstructed cerebral blood flow, leads to long-term neurological deficits and death. While neocortex is a commonly affected region with established preclinical models, less is known about deeper brain strokes, despite having unique neurological outcomes. We induced focal ischemic stroke while simultaneously monitors neuronal activity in awake behaving Thy1-GCaMP6f mice by delivering and collecting light through bilateral fiberoptic implants. Unilateral hippocampal stroke resulted in atypical mouse behavior coincident with ipsilesional terminal spreading depolarization (sustained increase in GCaMP6f fluorescence). Ischemia induced seizures that propagated to the contralesional hippocampus triggering a transient spreading depolarization (SD), predominantly in females. Hippocampal stroke impaired contextual fear conditioning acquired pre-stroke. Yet, 7 days post-stroke, contextual fear conditioning was only improved in mice with evidence of contralesional SD. Here, recovery of hippocampal function was lost by blunting peri-stroke SD with NMDAR antagonism, indicating that contralesional SD improves recovery following hippocampal stroke.

neuroscience↗

bioRxiv2022

Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack preventative treatments. Based on the observation that discrete seizures lead to local vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain (Farrell et al., 2016), we reasoned that similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of SUDEP, ibuprofen and nicardipine extended life. We also examined the potential role of spreading depolarization in the acute model of SUDEP. These data provide a proof of principle for the neurovascular hypothesis of SUDEP and the use of currently available treatments to prevent it.

neuroscience↗

bioRxiv2021

New neurons in old brains: A cautionary tale for the analysis of neurogenesis in post-mortem tissue.

Adult neurogenesis has primarily been examined in two key regions in the mammalian brain, the subgranular zone of the hippocampus and the subventricular zone. The proliferation and integration of newly generated neurons has been observed widely in adult mammalian species including the human hippocampus. Recent high-profile studies have suggested however, that this process is considerably reduced in humans, occurring in children but declining rapidly and nearly completely in the adult brain. In comparison, rodent studies also show age-related decline but a greater degree of proliferation of new neurons in adult animals. Here, we examine whether differences in tissue fixation, rather than biological difference in human versus rodent studies might account for the diminished levels of neurogenesis sometimes observed in the human brain. To do so we analyzed neurogenesis in the hippocampus of rats that were either perfusion-fixed or the brains extracted and immersion-fixed at various post-mortem intervals. We observed an interaction between animal age and the time delay between death and tissue fixation. While similar levels of neurogenesis were observed in young rats regardless of fixation, older rats had significantly fewer labeled neurons when fixation was not immediate. Furthermore, the morphological detail of the labeled neurons was significantly reduced in the delayed fixation conditions at all ages. This study highlights critical concerns that must be considered when using post-mortem tissue to quantify adult neurogenesis.

neuroscience↗

bioRxiv2020

The Neurovascular Basis of Postictal Amnesia

Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.

neuroscience↗

bioRxiv2019

Seizures cause sustained microvascular constriction associated with astrocytic and vascular smooth muscle Ca2+ recruitment

Previously we showed that seizures result in a severe hypoperfusion/hypoxic attack that results in postictal memory and behavioral impairments (Farrell et al., 2016). However, neither postictal changes in microvasculature nor Ca2+ changes in key cell-types controlling blood perfusion have been visualized in vivo, leaving essential components of the underlying cellular mechanisms unclear. Here we use two-photon microvascular and Ca2+ imaging in awake mice to show that seizures result in a robust vasoconstriction of cortical penetrating arterioles, which temporally mirrors the prolonged postictal hypoxia. The vascular effect was dependent on cyclooxygenase-2, as pre-treatment with ibuprofen prevented postictal vasoconstriction. Seizures caused a rapid elevation in astrocyte endfoot Ca2+ that was confined to the seizure period. Vascular smooth muscle cells displayed a significant increase in Ca2+ both during and following seizures, lasting up to 75 minutes. The temporal activities of two cell-types within the neurovascular unit lead to seizure-induced hypoxia.\n\nHighlightsO_LISeizures lead to equivalent levels of postictal hypoxia in both male and female mice\nC_LIO_LICalcium elevation in astrocyte endfeet is confined to the seizure\nC_LIO_LIPostictal vasoconstriction in awake mice is mediated by cyclooxygenase-2\nC_LIO_LICalcium elevation in vascular smooth muscle cells is enduring and correlates with vasoconstriction.\nC_LI

neuroscience↗

bioRxiv2018

Postsynaptic Pannexin-1 Facilitates Anandamide Uptake to Modulate Glutamate Release and Enhance Network Excitability

Prolonged neurotransmitter release following synaptic stimulation extends the time window for postsynaptic neurons to respond to presynaptic activity. This can enhance excitability and increase synchrony of outputs, but the prevalence of this at normally highly synchronous synapses is unclear. We show that the postsynaptic channel, pannexin-1 (Panx1) regulates prolonged glutamate release onto CA1 neurons. Block of postsynaptic (CA1 neuronal) Panx1 increased the frequency of glutamate neurotransmission and action potentials in these neurons following Schaffer collateral stimulation. When Panx1 was blocked, anandamide levels increase and activated transient receptor potential vanilloid 1 (TRPV1)-mediated glutamate release. This TRPV1-induced synaptic acitvity enhanced excitability and translated into a faster rate of TRPV1-dependent epileptogenesis induced by kindling. We conclude that Panx1 facilitates AEA clearance to maintain synchronous release onto CA1 neurons so that when AEA clearance is reduced, TRPV1 channels prolong glutamate neurotransmission to enhance network output to promote epileptiform activity.

neuroscience↗