Biology subjects

Gelinas, J. N.

Publications and source records attributed to Gelinas, J. N..

3 recordsLinked to original sources

bioRxiv2024

Closed-loop electrical stimulation to prevent focal epilepsy progression and long-term memory impairment

Interictal epileptiform discharges (IEDs) are ubiquitously expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes as most therapeutics target seizures. We show in a model of progressive hippocampal epilepsy that IEDs produce pathological oscillatory coupling which is associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expands the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human subjects with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation. One-Sentence SummaryTargeted closed-loop electrical stimulation prevents spread of the epileptic network and ameliorates long-term spatial memory deficits.

neuroscience↗

bioRxiv2021

A transient postnatal quiescent period precedes emergence of mature cortical dynamics

Mature neural networks synchronize and integrate spatiotemporal activity patterns to support cognition. Emergence of these activity patterns and functions is believed to be developmentally regulated, but the postnatal time course for neural networks to perform complex computations remains unknown. We investigate the progression of large-scale synaptic and cellular activity patterns across development using high spatiotemporal resolution in vivo electrophysiology in immature mice. We reveal that mature cortical processes emerge rapidly and simultaneously after a discrete but volatile transition period at the beginning of the second postnatal week of rodent development. The transition is characterized by relative neural quiescence, after which spatially distributed, temporally precise, and internally organized activity occurs. We demonstrate a similar developmental trajectory in humans, suggesting an evolutionarily conserved mechanism to transition network operation. We hypothesize that this transient quiescent period is a requisite for the subsequent emergence of coordinated cortical networks.

neuroscience↗

bioRxiv2020

The paradoxical effects of K+ channel gain-of-function are mediated by GABAergic neuron hypoexcitability and hyperconnectivity.

Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduced a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, found motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increased KNa currents in cortical excitatory and inhibitory neurons, there was a selective increase in the KNa current across subthreshold voltages in inhibitory neurons, particularly in those with non-fast spiking properties, resulting in impaired excitability and AP generation. We further observed evidence of synaptic rewiring associated with hyperexcitable networks, including increases in homotypic synaptic connectivity and the ratio of excitatory-to-inhibitory synaptic input. These findings support inhibitory neuron-specific mechanisms in mediating the epileptogenic effects of K+ channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/978841v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@110d6e1org.highwire.dtl.DTLVardef@8b63ddorg.highwire.dtl.DTLVardef@14972a9org.highwire.dtl.DTLVardef@106be1c_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

neuroscience↗