Project

Discipline

viral vectors; GABAergic synapse; Cre-dependent gene targeting; neostriatum; Parkinson's disease; globus pallidus; immuno-electron microscopy; interneuron; acetylcholine; GABAA receptor; optogenetics

Lead
In diesem Projekt wird die synaptische Übertragung in einem Kerngebiet des Gehirns morphologisch und funktionell untersucht, um die Symptome der Parkinson-Krankheit besser zu verstehen
Lay summary
Motorische und kognitive Vorgänge werden gleichzeitig in mehreren Schaltkreisen im Gehirn verarbeitet. Die Basalganglien sind tief im Gehirn lokalisiert. Der Hauptkern, das Neostriatum, bekommt laufend eine Kopie der Information, die in der Grosshirnrinde verarbeitet wird, und, unter Einfluss des Botenstoffes Dopamin, überarbeitet diese Information weiter, bevor sie zurück in die Grosshirnrinde geschickt wird. Diese Schlaufe ermöglicht unter anderem die Integration von emotionalen Zuständen in der Entstehung und Ausführung von Handlungen und Bewegungen.  Die Bedeutung der Basalganglien wird besonders ersichtlich bei der Parkinson-Krankheit, da die motorischen Symptome dieser degenerativen Erkrankung weitgehend auf dem Verlust der dopaminergen Übertragung im Neostriatum beruhen.  Es bleiben aber viele Fragen offen: z.B., wie wird die normale Funktion der Basalganglien auf zellulärer und molekularer Ebene reguliert; wie verändert sie sich pathologisch nach dem Verlust von Dopamin? Insbesondere weiss man sehr wenig über die funktionelle Organisation der GABAergen Übertragung im Neostriatum, obwohl dieser Neurotransmitter in 95% der Nervenzellen im Neostriatum vorkommt. Ebenso wenig weiss man über Wechselwirkungen zwischen GABAerger und Dopaminerger Übertragung im Neostriatum. Das Ziel dieses Forschungsprojekt ist, die molekulare und funktionelle Organisation der GABAergen Übertragung im Neostriatum der Maus morphologisch und elektrophysiologisch zu untersuchen, und die Konsequenzen einer experimentellen Ablation von Dopamin, als Modell der Parkinson-Krankheit, zu etablieren. Es wird erwartet, dass die GABAergen Neuronen im gesunden Zustand molekular-heterogene Schaltkreise etablieren, um die Aktivität verschiedener Netzwerke spezifisch zu regulieren, und dass diese Organisation infolge des Verlustes an Dopamin pathologisch re-organisiert wird. Ein besseres Verständnis dieser komplexen Vorgänge soll den Weg zu effektiverer Therapien der Parkinsonkrankheit verhelfen.

Direct link to Lay Summary

Last update: 04.04.2016

Active participation

Number	Title	Start	Funding scheme

The neostriatum (caudate nucleus and putamen) is the main input nucleus of the basal ganglia. It receives major glutamatergic afferents from the neocortex and thalamus, as well as a dense dopaminergic (DA) innervation from the substantia nigra, pars compacta. It projects to the substantia nigra, pars reticulata (direct pathway) and the external segment of the globus pallidus (GPe; indirect pathway), which in turn exert opposite effects on the thalamo-cortical system. Accordingly, the basal ganglia as a whole, and the striatum in particular (with a clear distinction between dorsal and ventral striatum), have been implicated in a vast array of brain functions and behaviors, including regulation of motor activity, planning and execution of motor and cognitive tasks, executive memory, skill learning, habit formation, reward processing, and addiction. Dysfunction of striatal circuits is causally related to major motor, cognitive, and emotional deficiencies. The degeneration of the nigro-striatal dopaminergic pathway in Parkinson’s disease (PD) is among the most prominent and best studied causes of striatal dysfunction, which eventually cause major motor and cognitive symptoms of the disease. The striatum is composed mainly of GABAergic principal cells (medium-spiny neurons; MSN) along with several subtypes of GABAergic and cholinergic interneurons, which modulate the activity and synchronization of MSN. So far, the local inhibitory synaptic circuits of the neostriatum remain poorly characterized. In particular, little is known about a possible cellular or subcellular segregation of various types of GABAergic inputs (collaterals from MSN, extrinsic projections, interneuron subtypes) onto MSN, as well as onto interneurons (forming possible disinhibitory circuits). Likewise, the organization of GABAergic circuits in the major functional subdivisions of the neostriatum (direct/indirect pathways; striosomes/matrix) is not established. These anatomical features are likely highly relevant for understanding potential alterations and reorganization of neostriatal GABAergic circuits in neurological and psychiatric disorders. On the postsynaptic level, GABAergic synapses are endowed with a vast diversity of GABAA receptor (GABAAR) subtypes, assembled from a family of 19 subunits (of which at least 12 are expressed in the neostriatum). GABAAR subtypes have distinct functional and pharmacological properties, and are subject to post-translational regulation in a subunit-specific manner. Therefore, GABAAR molecular heterogeneity might underlie the functional specialization of GABAergic transmission in neostriatal circuits and contribute to functional maladaptation under pathological conditions. The overreaching aim of this grant proposal is to explore the molecular organization of GABAergic synapses in the neostriatum and their alteration upon DA denervation (as a model of PD), using immunohistochemical and functional analysis in identified neurons and circuits of adult mice.The following specific aims will be pursued:1)What is the cellular (cell type-specific) and subcellular (dendritic, somatic, axonal) distribution pattern of major GABAAR subunits (a1-a5; b1-b3, g2, d) in the adult mouse neostriatum?2)Is there a cell type-specific and/or subcellular segregation of GABAergic inputs onto MSN and neostriatal interneurons, and does it correspond to the distribution of GABAAR subtypes?3)What are the functional and pharmacological properties of GABAergic synapses formed by fast-spiking interneurons and afferents from the GPe onto MSN, and how do they modulate their activity?4)How does a loss of afferent DA inputs in a model of Parkinson’s disease influence the anatomical and functional organization of GABAergic synapses onto MSN and striatal interneurons? The results are expected to highlight the cellular and subcellular organization of GABAARs in the adult mouse neostriatum, and therefore provide a baseline for investigating alterations in GABAergic circuits in disease states.