Mobiele menu

Role of Cerebellar Nuclei in Ataxia and Epilepsy: Causes, Consequences, Computations, and Cures

Projectomschrijving

Cerebellaire kernen in ataxie en epilepsy: van oorzaak tot behandeling
De neuronale afwijkingen aan de hersenen die leiden tot ataxie en epilepsie zijn slechts gedeeltelijk bekend. De rol van de cerebellaire kernen, welke centraal in de neuronale systemen van ataxie en epilepsie liggen, is nog niet bekend. Het is ons doel om op een innovatieve manier data uit mutante muizen en patiënten te integreren en met behulp van een nieuwe benadering voor brain-machine interfacing te modelleren, en zodoende om nieuwe neurochirurgische applicaties van stimulatie van de cerebellaire kernen voor de behandeling van ataxie en epilepsie te ontwikkelen.

Producten

Titel: STD-dependent and independent encoding of input irregularity as spike rate in a computational model of a cerebellar nucleus neuron
Auteur: Luthman J, Hoebeek FE, Maex R, Davey N, Adams R, De Zeeuw CI, Steuber V.
Magazine: Cerebellum
Titel: Strength and timing of motor responses mediated by rebound firing in the cerebellar nuclei after Purkinje cell activation.
Auteur: Witter L, Canto CB, Hoogland TM, de Gruijl JR, De Zeeuw CI.
Magazine: Frontiers in Neural Circuits
Titel: Silencing the majority of cerebellar granule cells uncovers their essential role in motor learning and consolidation.
Auteur: Galliano E, Gao Z, Schonewille M, Todorov B, Simons E, Pop AS, D'Angelo E, van den Maagdenberg AM, Hoebeek FE, De Zeeuw CI.
Magazine: Cell Reports
Titel: Climbing fiber input shapes reciprocity of Purkinje cell firing.
Auteur: Badura A, Schonewille M, Voges K, Galliano E, Renier N, Gao Z, Witter L, Hoebeek FE, Chédotal A, De Zeeuw CI.
Magazine: Neuron
Titel: The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice.
Auteur: Vinueza Veloz MF, Buijsen RA, Willemsen R, Cupido A, Bosman LW, Koekkoek SK, Potters JW, Oostra BA, De Zeeuw CI
Magazine: Genes, brain, and behavior
Titel: fMRI activities in the emotional cerebellum: a preference for negative stimuli and goal-directed behavior.
Auteur: Schraa-Tam CK, Rietdijk WJ, Verbeke WJ, Dietvorst RC, van den Berg WE, Bagozzi RP, De Zeeuw CI.
Magazine: Cerebellum
Titel: Stress, caffeine and ethanol trigger transient neurological dysfunction through shared mechanisms in a mouse calcium channelopathy.
Auteur: Raike RS, Weisz C, Hoebeek FE, Terzi MC, De Zeeuw CI, van den Maagdenberg AM, Jinnah HA, Hess EJ.
Magazine: Neurobiology of Disease
Titel: A potential role for the cerebellar nuclei in absence seizures.
Auteur: Parimala Alva, Lieke Kros, Reinoud Maex, Chris I De Zeeuw, Rod Adams, Neil Davey, Volker Steuber, Freek E Hoebeek
Magazine: BMC Neuroscience
Titel: Limited regional cerebellar dysfunction induces focal dystonia in mice.
Auteur: Raike RS, Pizoli CE, Weisz C, van den Maagdenberg AM, Jinnah HA, Hess EJ.
Magazine: Neurobiology of Disease
Titel: Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.
Auteur: Gao Z, Todorov B, Barrett CF, van Dorp S, Ferrari MD, van den Maagdenberg AM, De Zeeuw CI, Hoebeek FE.
Magazine: Journal of Neuroscience
Titel: PRRT2 mutation causes benign familial infantile convulsions.
Auteur: de Vries B, Callenbach PM, Kamphorst JT, Weller CM, Koelewijn SC, ten Houten R, de Coo IF, Brouwer OF, van den Maagdenberg AM.
Magazine: Neurology
Titel: Role of Synchronous Activation of Cerebellar Purkinje Cell Ensembles in Multi-joint Movement Control
Auteur: Tycho M. Hoogland, Jornt R. De Gruijl, Laurens Witter, Cathrin B. Canto, Chris I. De Zeeuw
Titel: Purkinje cell-specific ablation of Cav2.1 channels is sufficient to cause cerebellar ataxia in mice
Auteur: Todorov B, Kros L, Shyti R, Plak P, Haasdijk ED, Raike RS, Frants RR, Hess EJ, Hoebeek FE, De Zeeuw CI, van den Maagdenberg AM
Magazine: Cerebellum
Titel: Distributed synergistic plasticity and cerebellar learning.
Auteur: Gao Z, van Beugen BJ, De Zeeuw CI
Magazine: Nature Reviews Neuroscience
Titel: High frequency burst firing of granule cells ensures transmission at the parallel fiber to purkinje cell synapse at the cost of temporal coding.
Auteur: van Beugen BJ, Gao Z, Boele HJ, Hoebeek F, De Zeeuw CI.
Magazine: Frontiers in Neural Circuits

Verslagen


Samenvatting van de aanvraag

Over the past decades most studies aimed at elucidating the role of the cerebellum in the generation of ataxia and epilepsy have been focused on its cortex. Yet, our pilot data indicate that the cerebellar nuclei (CN) can play a prominent role in causing these syndromes and that they might form an ideal target to tackle these diseases at a therapeutic level. For example, we observed that epileptic activity can occur in the CN before a more generalized form of epilepsy occurs in the cerebral cortex. Here we propose to investigate the activities of CN neurons in both mouse models and/or patients suffering from deficits in the expression of their CACNA1A, CACNG2 or SCN1A genes which induce ataxia and epilepsy. Depending on the precise mutation, abnormal expression of either one of these genes can result in various levels of ataxia and/or epilepsy, and in several pilots we have observed abnormal spiking activities in the CN neurons of related mouse models. Using an approach of life sciences (ALW) and medical sciences (ZonMW) we will investigate the functional activity patterns of CN neurons and their effects on downstream activity in relation to motor coordination and absence seizures in global and cell type-specific, inducible Cacna1a, Cacng2 or Scn1a mouse mutants as well as in SCA6, SCA10, SMEI and GEFS+ patients. Based upon their differences in spatiotemporal activity patterns with controls we will complement these fundamental and clinical studies by developing a novel computational interface WhiskID modeling approach in the exact sciences (EW) so as to rescue the pathological spiking activities in their CN. Together these multidisciplinary studies should not only reveal new fundamental mechanisms underlying signal processing in the CN, but they should also elucidate how abnormalities in CN activities can lead to ataxia and/or epilepsy, and how they might be treated with a novel type of brain-machine interface.

Onderwerpen

Kenmerken

Projectnummer:
91210067
Looptijd: 100%
Looptijd: 100 %
2011
2017
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. F.E. Hoebeek PhD
Verantwoordelijke organisatie:
Erasmus MC