Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease.

Studying animal models furthers our understanding of Parkinson's disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson's disease in mice.

Voltage-gated sodium channels in genetic epilepsy: up and down of excitability.

The past two decades have witnessed a wide range of studies investigating genetic variants of voltage-gated sodium (NaV ) channels, which are involved in a broad spectrum of diseases, including several types of epilepsy. We have reviewed here phenotypes and pathological mechanisms of genetic epilepsies caused by variants in NaV α and ß subunits, as well as of some relevant interacting proteins (FGF12/FHF1, PRRT2, and Ankyrin-G). Notably, variants of all these genes can induce either gain- or loss-of-function of NaV leading to either neuronal hyperexcitability or hypoexcitability. We present the results of functional studies obtained with different experimental models, highlighting that they should be interpreted considering the features of the experimental system used. These systems are models, but they have allowed us to better understand pathophysiological issues, ameliorate diagnostics, orientate genetic counseling, and select/develop therapies within a precision medicine framework. These studies have also allowed us to gain insights into the physiological roles of different NaV channels and of the cells that express them. Overall, our review shows the progress that has been made, but also the need for further studies on aspects that have not yet been clarified. Finally, we conclude by highlighting some significant themes of general interest that can be gleaned from the results of the work of the last two decades.

Orientation of Temporal Interference for Non-invasive Deep Brain Stimulation in Epilepsy.

In patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on non-penetrating surface electrodes, namely an orientation-tunable form of temporally interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of Pulse-width-modulation of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally invasive temporally interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue and overcoming several limitations of other non-invasive stimulation methods in epilepsy, such as transcranial magnetic stimulation (TMS).

The Kainic Acid Models of Temporal Lobe Epilepsy.

Experimental models of epilepsy are useful to identify potential mechanisms of epileptogenesis, seizure genesis, comorbidities, and treatment efficacy. The kainic acid (KA) model is one of the most commonly used. Several modes of administration of KA exist, each producing different effects in a strain-, species-, gender-, and age-dependent manner. In this review, we discuss the advantages and limitations of the various forms of KA administration (systemic, intrahippocampal, and intranasal), as well as the histologic, electrophysiological, and behavioral outcomes in different strains and species. We attempt a personal perspective and discuss areas where work is needed. The diversity of KA models and their outcomes offers researchers a rich palette of phenotypes, which may be relevant to specific traits found in patients with temporal lobe epilepsy.