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Minichiello group shows neurotrophin signalling dysfunction in a subset of cerebellar granule cells triggers ataxia

Department

A new study from the Minichiello group, published recently in the journal Biology, has shown that dysfunction in BDNF-TrkB signalling, restricted to a specific subset of cerebellar granule cells, is sufficient to generate ataxic symptoms

The connections between granule cells and Purkinje cells are extensive, with each granule cell synapsing on 400 Purkinje cells and each Purkinje cell receiving input from 50,000 granule cells in the mouse cerebellum. Therefore, by deleting Ntrk2 (the gene that encodes TrkB) in a subset of granule cells, researchers disrupted signalling in numerous Purkinje cells. In the schematic, intact synapses between granule cells and Purkinje cells are marked by red circles, while yellow circles reflect synapses through which communication is affected by the ablated BDNF-TrkB signalling. Figure created in BioRender.
The connections between granule cells and Purkinje cells are extensive, with each granule cell synapsing on 400 Purkinje cells and each Purkinje cell receiving input from 50,000 granule cells in the mouse cerebellum. Therefore, by deleting Ntrk2 (the gene that encodes TrkB) in a subset of granule cells, researchers disrupted signalling in numerous Purkinje cells. In the schematic, intact synapses between granule cells and Purkinje cells are marked by red circles, while yellow circles reflect synapses through which communication is affected by the ablated BDNF-TrkB signalling. Figure created in BioRender.

While motor incoordination in patients suffering from ataxia disorders is primarily linked to the dysfunction and degeneration of cerebellar Purkinje cells (PCs), this study highlights how signalling dysfunction in a subset of cerebellar granule cells (GCs), which provide input to PCs, can trigger ataxia symptoms.

Brain-derived neurotrophic factor (BDNF)-TrkB signalling-activated pathways have been implicated in ataxia disorders. In spinocerebellar ataxia 6 (SCA6), for example, reduced BDNF-TrkB signalling has been linked to PC dysfunction and motor incoordination. However, the TrkB receptor is also present in GCs, which have extensive connections with PCs, suggesting that impaired BDNF-TrkB signalling in GCs would also negatively affect the function of PCs and possibly contribute to symptoms of motor incoordination in ataxia disorders.

To prove this, the researchers removed the Ntrk2 (the gene encoding the TrkB receptor) specifically from enkephalinergic precursor-derived cerebellar granule cells in mice. The consequences of BDNF-TrkB signalling ablation in this subpopulation of neurons were enough to induce ataxia symptoms such as motor incoordination. These findings find support in the human disorder. Specifically, the researchers, by exploring a publicly available transcriptomic dataset from the cerebella of healthy humans and patients with ataxia telangiectasia (AT), found that NTRK2 expression was reduced in the GCs of the AT cerebella but not PC cells, suggesting that GC dysfunction may also contribute to cerebellar ataxias.

Therefore, this work suggests that we must look beyond PCs as the sole driver of motor deficits in ataxia disorders and consider the role granule cell dysfunction may play in these conditions.

This work, authored by a DPhil student, Elena Eliseeva, and Dr Yaseen Mohd Malik in the Department, is entitled “Ablation of TrkB from Enkephalinergic Precursor-Derived Cerebellar Granule Cells Generates Ataxia” and can be read here: https://doi.org/10.3390/biology13080637.

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