Marylka Uusisaari from the Erasmus Medical Centre, Rotterdam joins us for a special journal club session.
Anatomical understanding of the neuronal circuitry, comparable to electronic chip blueprint underlies theories and models of computational capabilities of various brain structures. The fundamental and essential nature of this knowledge is recently gaining visibility in the form of large-scale connectomic mapping initiatives. Their work aims (among others) to define the communication pathways between neurons, most commonly delineated in terms of axonal termination spaces and their overlaps with the target neurons’ dendritic fields.
The axo-dendritic or axo-somatic chemical synaptic connection is not, however, the only mechanism for fast interneuronal communication, as gap junctions linking neighbouring neurons provide the means for electrical signal propagation and synchronisation of spiking activity. A prime example of a structure where this mechanism plays a key role in shaping network activity is the inferior olive (IO), a nucleus in the brainstem integrating multimodal sensorimotor input and providing the climbing fibre input to the cerebellum. Intriguingly, there seem to be no local chemical synapses within the IO; instead, the coherence of inter-olivary network relies entirely on gap junctional communication. Thus, it is of key interest to define the anatomical arrangement of IO cells in respect to each other, as the amount of electrical coupling between individual IO cells - defining the emerging spatio-temporal patterns of olivo-cerebellar activity - must depend on the extent of dendritic overlap.
It is generally assumed that the IO cells are spherical neurons interspersed homogeneously throughout the nucleus, with the strength of electrical coupling decreasing with increasing inter-somata distance. However, this assumption has not been rigorously examined until now; and indeed, early anatomical works (Sotelo et al., 1974) described the olive as formed of segregated clusters of olivary cells.
To gain insight into the possible inhomogeneity and anisotropy present on anatomical level in the IO, we employed a novel “sparse viral labelling” technique that preserves the flexibility of genetically targetable staining but results in a sparse, Golgi-stain-like labelling of neurons. This method allows detailed reconstruction of large number of neurons in thick brain sections and thereby quantitative assessment of their dendritic morphology in respect to the boundaries of the IO as well as to the neighbouring cohort of IO cells.
Examining a large number of reconstructed cells as well as the overall arrangement of thousands of IO cell bodies revealed that while closely positioned IO cells’ dendritic fields may overlap to a great extent, the inter-somatic distance is not necessarily indicative of overlap. In contrast, IO cells can show strong avoidance regarding their neighbouring cells’ dendritic fields, suggesting that the functional clustering of IO as well as their axonal activity (i.e., the climbing fibre) is defined by the IO cell dendrite arrangement. Such non-uniform neuronal arrangement calls for re-evaluation of our hypotheses regarding the origins of cerebellar complex spike synchrony.