The Mesodiencephalic Junction as a Central Hub for Cerebro-Cerebellar Communication

Most studies investigating the impact of cerebral cortex (CC) onto the cerebellum highlight the role of the pontine mossy fibre system. However, cerebro-cerebellar communication may also be mediated by the olivary climbing fibres via a hub in the mesodiencephalic junction (MDJ). Here, we show that rostromedial and caudal parts of mouse CC predominantly project to the principal olive via the rostroventral MDJ and that more rostrolateral CC regions prominently project to the rostral medial accessory olive via the caudodorsal MDJ. Moreover, transneuronal tracing results show that the cerebellar nuclei innervate the olivary-projecting neurons in the MDJ that receive input from CC, and that they adhere to the same topographical relations. By unravelling these topographic and dense, mono- and disynaptic projections from the CC through the MDJ and inferior olive to the cerebellum, this work establishes that cerebro-cerebellar communication can be mediated by both the mossy fibre and climbing fibre system.

WHAT ADVANCEMENTS IN CLINICAL NEUROSCIENCES NEED TO OCCUR IN THE NEXT 10 YEARS?

Introduction: Temporal lobe epilepsy (TLE) is the commonest focal epilepsy. Acquired TLE is considered to occur as the result of a 3-phase process called epileptogenesis. Firstly, an ‘epileptogenic event’ occurs, for example traumatic brain injury. Next follows a latent period whereby hyperexcitable networks form and lower the seizure threshold. Finally, TLE emerges. The objective of this review is to investigate how gene dysregulation drives hyperexcitability during epileptogenesis. Methods: Searches were conducted using keywords and medical subject headings on bibliographic databases and complemented by Google searches and manual revision of reference lists of retrieved articles. Results: Multiple pathogenic processes occur during the latent phase of epileptogenesis, before acquired TLE is diagnosed. These are hippocampal sclerosis, synaptic reorganisation including mossy fibre sprouting, neuroinflammation, aberrant neurogenesis and astrogliosis. Furthermore, epigenetic signalling pathways including DNA methylation, histone modifications, transcriptional and post-transcriptional dysregulation drive these pathogenic brain changes. Discussion: The epigenetic pathways that drive pathogenic brain changes following epileptogenic events are potential therapeutic targets for novel antiepileptic drugs. Targeting molecular pathways could prevent many cases of acquired TLE by halting epileptogenesis in the latent phase, meaning new therapies for acquired TLE have the potential to be antiepileptogenic rather than simply anticonvulsant.

A computational model of homeostatic cerebellar compensation of ageing in vestibulo-ocular reflex adaptation

The vestibulo-ocular reflex (VOR) stabilises vision during head motion. Age-related structural changes predict a linear VOR decay, whereas epidemiological data show a non-linear temporal profile. Here, we model cerebellar-dependent VOR adaptation to link structural and functional changes throughout ageing. We posit that three neurosynaptic factors codetermine VOR ageing patterns: electrical coupling between inferior olive neurons, intrinsic plasticity at Purkinje cell synapses, and long-term spike timing dependent plasticity at parallel fibre - Purkinje cell synapses as well as mossy fibre - medial vestibular nuclei synapses. Our cross-sectional simulations show that long-term plasticity acts as a global homeostatic mechanism mediating the non-linear temporal profile of VOR. Our results also suggest that intrinsic plasticity at Purkinje cells acts as a local homeostatic mechanism sustaining VOR at old ages. Importantly, longitudinal simulations show that residual fibres coding for the peak and trough of the VOR cycle constitute a predictive hallmark of VOR ageing trajectories.

Single synapses control mossy cell firing

The function of mossy cells (MCs) in the dentate gyrus has remained elusive. Here we determined the functional impact of single mossy fibre (MF) synapses on MC firing in mouse entorhino-hippocampal slice cultures. We stimulated single MF boutons and recorded Ca2+ transients in the postsynaptic spine and unitary excitatory postsynaptic potentials (EPSPs) at the MC soma. Synaptic responses to single presynaptic stimuli varied strongly between different MF synapses, even if they were located on the same MC dendrite. Synaptic strengths ranged from subthreshold EPSPs to direct postsynaptic action potential (AP) generation. Induction of synaptic plasticity at these individual MF synapses resulted in potentiation or depression depending on the initially encountered synaptic state, indicating that synaptic transmission at MF synapses on MCs is determined by their previous functional history. With these unique functional properties MF-MC synapses control MC firing individually thereby enabling modulation of the dentate network by single granule cells.

Physical determinants of vesicle mobility and supply at a central synapse

Encoding continuous sensory variables requires sustained synaptic signalling. At several sensory synapses, rapid vesicle supply is achieved via highly mobile vesicles and specialized ribbon structures, but how this is achieved at central synapses without ribbons is unclear. Here we examine vesicle mobility at excitatory cerebellar mossy fibre synapses which sustain transmission over a broad frequency bandwidth. Fluorescent recovery after photobleaching in slices from VGLUT1Venus knock-in mice reveal 75% of VGLUT1-containing vesicles have a high mobility, comparable to that at ribbon synapses. Experimentally constrained models establish hydrodynamic interactions and vesicle collisions are major determinants of vesicle mobility in crowded presynaptic terminals. Moreover, models incorporating 3D reconstructions of vesicle clouds near active zones (AZs) predict the measured releasable pool size and replenishment rate from the reserve pool. They also show that while vesicle reloading at AZs is not diffusion-limited at the onset of release, diffusion limits vesicle reloading during sustained high-frequency signalling.