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Extensive researches have deepened knowledge on the role of synaptic components in epileptogenesis, but limited attention has been devoted to the potential implication of the cytoskeleton. The study of the development of epilepsy and hyperexcitability states involves molecular, synaptic, and structural alterations of neuronal bioelectric activity. In this paper we aim to explore the neurobiological targets involved in microtubule functioning and cytoskeletal transport, i.e. how dynamic scaffolding of microtubules can influence neuronal morphology and excitability, in order to suggest a potential role for microtubule dynamics in the processes turning a normal neuronal network in a hyperexcited one. Pathophysiological alterations of microtubule dynamics inducing neurodegeneration, network remodeling and relative impairment on synaptic transmission were overviewed. Recent researches were reported on the phosphorylation state of microtubule-associated proteins such as tau in neurodegenerative diseases and epileptic states, but also on the effect of microtubule-active agents influencing cytoskeleton destabilization in epilepsy models. The manipulation of microtubule polymerization was found effective in the modulation of hyperexcitability. In addition, it was considered the importance of microtubules and related neurotrophic factors during neural development since they are essential for the formation of a properly functional neuronal network. Otherwise, this can lead to cognitive deficits, hyperexcitability phenomena and neurodevelopmental disorders. Lastly, we evaluated the role of microtubule dynamics on neuronal efficiency considering their importance in the transport of mitochondria, cellular elements fulfilling energy requirements for neuronal activity, and a putative influence on cannabinoid-mediated neuroprotection. This review provides novel perspectives for the implication of microtubule dynamics in the development of epileptic phenomena. [ABSTRACT FROM AUTHOR]

Endocannabinoid system is considered a relevant player in the regulation of neuronal excitability, since it contributes to maintaining the balance of the synaptic ionic milieu. Perturbations to bioelectric conductances have been implicated in the pathophysiological processes leading to hyperexcitability and epileptic seizures. Cannabinoid influence on neurosignalling is exerted on classic receptor-mediated mechanisms or on further molecular targets. Among these, transient receptor potential vanilloid (TRPV) are ionic channels modulated by cannabinoids that are involved in the transduction of a plethora of stimuli and trigger fundamental downstream pathways in the post-synaptic site. In this review, we aim at providing a brief summary of the most recent data about the cross-talk between cannabinoid system and TRPV channels, drawing attention on their role on neuronal hyperexcitability. Then, we aim to unveil a plausible point of interaction between these neural signalling systems taking into consideration nitric oxide, a gaseous molecule inducing profound modifications to neural performances. From this novel perspective, we struggle to propose innovative cellular mechanisms in the regulation of hyperexcitability phenomena, with the goal of exploring plausible CB-related mechanisms underpinning epileptic seizures. [ABSTRACT FROM AUTHOR]

The presence of nitric oxide (NO) synthase and of soluble guanylyl cyclase, the main NO-activated metabolic pathway, has been demonstrated in many cells of the subthalamic nucleus. In this study, the effects induced on the firing of 96 subthalamic neurons by microiontophoretically administering drugs modifying NO neurotransmission were explored in anaesthetized rats. Recorded neurons were classified into regularly and irregularly discharging on the basis of their firing pattern. Nω-nitro-l-arginine methyl ester (L-NAME; a NO synthase inhibitor), 3-morpholino-sydnonimin-hydrocloride (SIN-1; a NO donor), S-nitroso-glutathione (SNOG; another NO donor) and 8-Br-cGMP (a cell-permeable analogue of cGMP, the main second-messenger of NO neurotransmission) were iontophoretically applied while performing single-unit extracellular recordings. The activity of most neurons was influenced in a statistically significant way: in particular, both current-related inhibitory L-NAME-induced effects (20/39 tested cells) and excitatory effects of SIN-1 (25/41 tested neurons), SNOG (19/32 tested cells) and 8-Br-cGMP (13/19 tested neurons) were demonstrated. Neither statistically significant differences between the responses of regularly and irregularly discharging cells, nor specific topographical clustering of responding neurons, were demonstrated. Neurons administered drugs oppositely modulating the NO neurotransmission often displayed responses to only one treatment. We hypothesize that NO neurotransmission could exert a modulatory influence upon subthalamic neurons, with a prevalent excitatory effect. However, in the light of the presence of some responses of opposite sign to the same drug displayed by different subthalamic neurons, more complex effects of NO neurotransmission could be suggested, probably due to interactions with other classical neurotransmitter systems. [ABSTRACT FROM AUTHOR]

Abstract: The effects induced on the discharge of subthalamic spontaneously active neurons by inhibiting the enzyme nitric oxide synthase was studied in two groups of urethane-anesthetized rats. In the first group of animals (n =10), the activity of subthalamic single units was recorded before and after the systemic administration of 7-nitro-indazole (7-NI, 50mg/kg i.p.), a selective inhibitor of neuronal nitric oxide synthase. In the second group of rats (n =15), Nω-nitro-l-arginine methyl ester (L-NAME), another inhibitor of nitric oxide synthase, was iontophoretically administered while performing single unit extracellular recordings. The activity of most tested spontaneously discharging neurons (8/10) was influenced by 7-NI administration, which always caused a statistically significant decrease in the firing rate of the responsive cells. In contrast, the iontophoretic administration of L-NAME, although influencing many cells (24/32), did not have univocal effects: in fact, 18 cells were inhibited while 6 neurons were excited in a statistically significant manner. We hypothesize that nitric oxide neurotransmission could exert a tonic modulatory influence upon spontaneously discharging subthalamic neurons, with a prevalent excitatory effect. [Copyright &y& Elsevier]

Nitric oxide (NO) is a fascinating signalling molecule implicated in a plethora of biological functions, especially at the synaptic level. Exploring neurotransmission in the hippocampus could be instrumental in the individuation of putative targets for nitric-oxide mediated neuromodulation, especially in terms of the potential repercussions on fundamental processes i.e. synaptic plasticity and excitability-related phenomena. Among these targets, endovanilloid signalling constitutes an object of study since Transient Receptors Vanilloid type 1 (TRPV1) channels possess a NO-sensitive gate modulating its activation. Also, NO has been referred to as a mediator for numerous endocannabinoid effects. Notwithstanding, the linkage between TRPV1 and NO systems in neuromodulation still remains elusive. To this end, we aim at investigating the involvement of TRPV1 in nitric oxide-mediated influence on hippocampal processes. Electrophysiological whole-cell recordings in CA1 pyramidal neurons were applied to evaluate excitatory neurotransmission in rat brain slices. Indeed, miniature excitatory postsynaptic currents (mEPSCs) were analysed upon pharmacological manipulation of TRPV1 and NO signalling pathways. In detail, only the administration of the specific TRPV1 exogenous agonist – capsaicin - reduced the frequency and amplitude of mEPSC similarly to the inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (7NI). In contrast, capsazepine, TRPV1 antagonist, does not influence excitatory transmission. The combined TRPV1 activation and nNOS blockade confirm the presence of a putative common mechanism. When we administered the endovanilloid-endocannabinoid ligand, i.e. anandamide, we unveiled a potentiation of neurotransmission that was selectively reverted by 7NI. Our data suggest that nitric oxide influences TRPV1 hippocampal signalling since these channels are not constitutively active, but can be "on-demand" activated to modulate excitation in CA1 pyramidal neurons, and that this effect is linked to nitric oxide production. [Display omitted] • Nitric oxide production modulates excitatory transmission in CA1 pyramidal neurons. • TRPV1 influence nitrergic modulation of miniature excitatory post-synaptic currents. • Nitrergic intracellular levels are correlated with on-demand TRPV1-CB1 signaling. [ABSTRACT FROM AUTHOR]