Impact of unilateral maximal dentate activation on nitrergic neuron distribution in the hippocampus, entorhinal cortex, amygdala and habenula

Bombardi, Cristiano, Colangeli, Roberto, Casarrubea, Maurizio, De Deurwaerdère, Philippe, Crunelli, Vincenzo ORCID: https://orcid.org/0000-0001-7154-9752 and Di Giovanni, Giuseppe 2025. Impact of unilateral maximal dentate activation on nitrergic neuron distribution in the hippocampus, entorhinal cortex, amygdala and habenula. Brain Organoid and Systems Neuroscience Journal , 100038. 10.1016/j.bosn.2025.100038

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Abstract

Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy involving the hippocampus. While hippocampal circuits have been extensively studied, increasing evidence suggests that extrahippocampal structures, including the amygdala and habenula, may contribute to seizure propagation and epileptogenesis. Among modulators of excitability, nitric oxide (NO) is a key regulator, although its role in mTLE remains controversial, with both pro- and anticonvulsant effects reported. We used maximal dentate activation (MDA) in the dentate gyrus, elicited by repeated unilateral perforant path stimulation in rats, a well-established model for studying early mechanisms of epileptogenesis in mTLE. Repeated stimulation progressively shortened MDA onset latency and prolonged seizure duration, reflecting enhanced network excitability. To assess acute nitrergic alterations, an exploratory neuronal NO synthase (nNOS) and NADPH-diaphorase (NADPH-d) histochemical study wase performed in the hippocampus, entorhinal cortex, amygdala and habenula to determine whether repeated seizures could induce early changes in nitrergic neuronal expression. Histochemical analysis revealed region- and layer-specific changes in nitrergic neurons after MDA. In CA1 and CA3, reductions were observed in the stratum oriens, accompanied by an increased density in the CA3 pyramidal layer. The subiculum exhibited a depletion driven by a decrease of nitrergic neurons in the hemisphere contralateral to the stimulation, whereas the entorhinal cortex, basolateral amygdala and medial habenula were largely unaffected. In the lateral habenula, MDA did not alter the overall mean of the density of nitrergic neurons, but it increased it in the stimulated hemisphere and decreased it in the contralateral one. This preliminary study reveals adaptations that may indicate a sensitivity of nitrergic neurons to paroxysmal dentate activity and provide a basis for further exploring the potential involvement of NO-related pathways in limbic network responses and TLE-relevant mechanisms and treatments.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2025-12-14
Publisher:	Elsevier
ISSN:	2949-9216
Date of First Compliant Deposit:	18 December 2025
Date of Acceptance:	14 December 2025
Last Modified:	18 Dec 2025 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/183346

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