Biology subjects

Coulter, D. A.

Publications and source records attributed to Coulter, D. A..

3 recordsLinked to original sources

bioRxiv2025

Reducing ventral hippocampal CA1/subiculum hyperexcitability restores social memory and alleviates anxiety-related behavior in a mouse model of temporal lobe epilepsy

BackgroundInterictal cognitive and affective comorbidities in temporal lobe epilepsy (TLE) often remain refractory to seizure-directed therapies. We tested the causal role of ventral hippocampal CA1/subiculum (vCA1/Sub) hyperexcitability in social memory failure and anxiety-related behavior, and whether normalizing principal-cell excitability restores function. MethodsIn pilocarpine-treated mice we combined blinded behavioral assays (social approach/discrimination, open field, olfaction), whole-cell recordings from mCherry-labeled vCA1/Sub principal neurons, alveus stimulation to assay synaptic inhibition/excitation, immunohistochemistry for parvalbumin (PV) and somatostatin (SST) interneurons, and chemogenetic control of excitability (hM3Dq in controls; hM4Di and KORD in epileptic mice). Missing behavioral outcomes were handled by multiple imputation with bootstrapping; pooled analyses used ANOVA, mixed-effects models, and logistic regression. ResultsEpileptic mice showed preserved social approach but impaired social discrimination, with intact detection of social odors. Regular-spiking and bursting vCA1/Sub neurons exhibited depolarized resting membrane potential and reduced synaptically driven hyperpolarizations during alveus stimulation, indicating disinhibition; PV and SST interneuron densities were reduced in stratum oriens. Chemogenetic manipulation bidirectionally tuned excitability: bath CNO depolarized hM3Dq-expressing cells, whereas it hyperpolarized hM4Di-expressing cells by [~]5 mV and decreased current-evoked spiking. In vivo, inhibiting vCA1/Sub principal cells (hM4Di or KORD activation) increased the probability of successful social discrimination in epileptic mice without altering investigation time; neither CNO nor salvinorin B affected unDREADDed animals. In the open field, epileptic mice displayed reduced center preference and high-velocity bouts; vCA1/Sub inhibition normalized center preference and movement toward control values. Center preference predicted social discrimination in DREADDed epileptic mice, linking anxiety-related behavior to vCA1/Sub excitability. ConclusionsvCA1/Sub hyperexcitability drives interictal social memory and anxiety-related deficits in chronic TLE. Reducing principal-cell excitability restores behavior despite interneuron loss, supporting a model in which ventral hippocampal output can be retuned to rescue cognition. These results nominate neuromodulation of vCA1/Sub as a strategy to improve quality of life in epilepsy.

neuroscience↗

bioRxiv2024

Chemogenetic Breakdown of the Dentate Gate Causes Seizures and Spatial Memory Deficits

The dentate gyrus has often been posited to act as a gate that dampens highly active afferent input into the hippocampus. Effective gating is thought to prevent seizure initiation and propagation in the hippocampus and support learning and memory processes. Pathological changes to DG circuitry that occur in temporal lobe epilepsy (TLE) can increase DG excitability and impair its gating ability which can contribute to seizures and cognitive deficits. There is evidence that TLE pathologies and seizures may independently contribute to learning and memory deficits in TLE through distinct mechanisms. These two factors are difficult to untangle since TLE pathologies can drive seizures, and seizures can worsen TLE pathologies. Here we assessed whether chemogenetically increasing dentate granule cell (DGC) excitability was enough to break down the dentate gate in the absence of TLE pathologies. We found that increasing excitability specifically in DGCs caused seizures in non-epileptic mice. Importantly, due to the modulatory nature of DREADD effects, seizures were driven by intrinsic circuit activity rather than direct activation of DGCs. These seizures resulted in a spatial memory deficit when induced after training in the spatial object recognition task and showed stereotypical patterns of activity in miniscope calcium recordings. Our results provide direct support for the dentate gate hypothesis since seizures could be induced in non-epileptic animals by artificially degrading the dentate gate with chemogenetics in the absence of epilepsy pathologies.

neuroscience↗

bioRxiv2024

Prolonged Hyperactivity Elicits Massive and Persistent Chloride Ion Redistribution in Subsets of Cultured Hippocampal Dentate Granule Cells

Chloride ions play a critical role in neuronal inhibition through the activity of chloride-permeable GABAA receptor channels. Ion transporters, chloride channels, and immobile ion species tightly regulate intracellular chloride concentrations. Several studies related to epilepsy suggest that chloride extrusion function may decrease in an activity-dependent manner. Consequently, it is crucial to investigate whether intense neuronal activity, as observed during status epilepticus, could lead to sustained increases in intracellular chloride levels in neurons, which in turn could contribute to epilepsy-associated hyperexcitability. This study utilized the chloride sensitive indicator (6-Methoxyquinolinio) acetic acid ethyl ester bromide (MQAE) combined with fluorescence lifetime imaging (FLIM) to examine whether application of the convulsant, pilocarpine, a muscarinic acetylcholine receptor agonist, could induce synchronous epileptiform activity and elevate intracellular chloride concentrations in hippocampal slice cultures. Using a Gaussian mixture model, we identified a multimodal distribution of intracellular chloride levels among neurons, with a significant subset of these cells exhibiting massive and prolonged (days) chloride accumulation. The combination of multicellular imaging and statistical analysis served as a powerful tool for studying the emergence of multiple, distinct populations of neurons in pathological conditions, in contrast to homogeneous populations evident under control conditions. HighlightsO_LIMaintaining low [Cl-]in is important for inhibitory function, however, hyperactivity, such as that seen in epilepsy, may lead to elevated [Cl-]in. C_LIO_LIPilocarpine induces hyperactivity in dentate granule cells (DGCs) in hippocampal organotypic slice cultures. C_LIO_LIMulticellular imaging using a chloride sensing dye with a fluorescence lifetime imaging approach revealed that [Cl-]in is elevated in a subpopulation of DGCs. C_LIO_LIGaussian mixture model analysis is a powerful tool for studying the emergence of cellular heterogeneity in a pathological condition. C_LI

neuroscience↗