Biology subjects

Joksimovic, S. M.

Publications and source records attributed to Joksimovic, S. M..

4 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↗

bioRxiv2025

Facilitation of Cav3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia

The CaV3.2 isoform of T-type voltage-gated calcium channels plays a crucial role in regulating the excitability of nociceptive neurons; the endogenous molecules that modulate its activity, however, remain poorly understood. Here, we used serum proteomics and patch-clamp physiology to discover a novel peptide albumin (1-26) that facilitates channel gating by chelating trace metals that tonically inhibit CaV3.2 via H191 residue. Importantly, serum also potently modulated T-currents in human and rodent dorsal root ganglion (DRG) neurons. In vivo pain studies revealed that injections of serum and albumin (1-26) peptide resulted in robust mechanical and heat hypersensitivity. This hypersensitivity was abolished with a T-channel inhibitor, in CaV3.2 null mice and in CaV3.2 H191Q knock-in mice. The discovery of endogenous chelators of trace metals in the serum deepens our understanding of the role of CaV3.2 channels in neuronal hyperexcitability and may facilitate the design of novel analgesics with unique mechanisms of action.

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↗

bioRxiv2022

CaV3.1 T-type calcium channels regulate spatial memory processing in the dorsal subiculum

The dorsal subiculum (dSub) is one of the key structures responsible for the formation of hippocampal memory traces but the contribution of individual ionic currents to its cognitive function is not well studied. Although we recently reported that low-voltage-activated T-type calcium channels (T-channels) are crucial for the burst firing pattern regulation in the dSub pyramidal neurons, their potential role in learning and memory remains unclear. Here we used in vivo local field potential recordings and miniscope calcium imaging in freely behaving mice coupled with pharmacological and genetic tools to address this gap in knowledge. We show that the CaV3.1 isoform of T-channels is critically involved in controlling neuronal activity in the dSub in vivo. Altering burst firing pattern by inhibiting T-channel activity markedly affects calcium dynamics, synaptic plasticity, neuronal oscillations and phase-amplitude coupling in the dSub, thereby disrupting spatial learning. These results provide a crucial causative link between the CaV3.1 channels, burst firing activity of dSub neurons and memory processing, thus further supporting the notion that changes in neuronal excitability regulate memory trace formation. We posit that subicular CaV3.1 T-channels could be a promising novel drug target for cognitive disorders.

neuroscience↗