Biology subjects

Bak, A. N.

Publications and source records attributed to Bak, A. N..

3 recordsLinked to original sources

bioRxiv2026

Discovery of the Honeycomb Synapse in Spinal Motor Circuits

The structural and molecular diversity of synapses in the nervous system contributes to the specialisation of neural circuits underlying diverse behaviours. We have discovered a morphologically distinct postsynaptic specialisation in the mammalian spinal cord. We have named this the Honeycomb Synapse based on its elaborate postsynaptic nanostructure, comprising rings formed of ~6 scaffolding protein domains that create multiple perforations throughout the large postsynaptic domain. Analysis of the organisation of other synaptic proteins reveals that Honeycomb Synapses harbour mixed signalling properties structurally facilitated by a postsynaptic scaffold matrix supporting chemical transmission, with gap junction proteins occupying some of the perforations. We reveal anatomical diversity in the presence of Honeycomb Synapses on populations of -motoneurons across the lumbar spinal cord in mice from approximately 2 weeks of age through to adulthood. The Honeycomb Synapse was found to be a subtype of synapse within the Ia afferent monosynaptic stretch reflex circuit. Finally, we have identified that Honeycomb Synapses are highly vulnerable to degeneration in two different genetically engineered mouse models of Amyotrophic Lateral Sclerosis (ALS), contributing to monosynaptic stretch reflex circuit dysfunction. These findings suggest that synaptic diversity within circuits may confer selective vulnerability to distinct synaptic subclasses.

neuroscience↗

bioRxiv2024

TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-NLS model of Amyotrophic Lateral Sclerosis

A hyperexcitability of the motor system is consistently observed in Amyotrophic Lateral Sclerosis (ALS) and has been implicated in the disease pathogenesis. What drives this hyperexcitability in the vast majority of patients is unknown. This is important to know as existing treatments simply reduce all neuronal excitability and fail to distinguish between pathological changes and important homeostatic changes. Understanding what drives the initial pathological changes could therefore provide better treatments. One challenge is that patients represent a heterogeneous population and the vast majority of cases are sporadic. One pathological feature that almost all ([~]97%) cases (familial and sporadic) have in common is cytoplasmic aggregates of the protein TDP-43 which is normally located in the nucleus. In our experiments we investigated whether this pathology was sufficient to increase neuronal excitability and the mechanisms by which this occurs. We used the TDP-43({Delta}NLS) mouse model which successfully recapitulates this pathology in a controllable way. We used in vivo intracellular recordings in this model to demonstrate that TDP-43 pathology is sufficient to drive a severe hyper-excitability of spinal motoneurones. Reductions in soma size and a lengthening and constriction of axon initial segments were observed, which would contribute to enhanced excitability. Resuppression of the transgene resulted in a return to normal excitability parameters by 6-8 weeks. We therefore conclude that TDP-43 pathology itself is sufficient to drive a severe but reversible hyperexcitability of spinal motoneurones.

neuroscience↗

bioRxiv2022

Cytoplasmic TDP-43 accumulation drives changes in C-bouton number and size in a mouse model of sporadic Amyotrophic Lateral Sclerosis

An altered neuronal excitability of spinal motoneurones has consistently been implicated in Amyotrophic Lateral Sclerosis (ALS) leading to several investigations of synaptic input to these motoneurones. One such input that has repeatedly been shown to be affected is a population of large cholinergic synapses terminating mainly on the soma of the motoneurones referred to as C-boutons. Most research on these synapses during disease progression has used transgenic Superoxide Dismutase 1 (SOD1) mouse models of the disease which have not only produced conflicting findings, but also fail to recapitulate the key pathological feature seen in ALS; cytoplasmic accumulations of TAR DNA-binding protein 43 (TDP-43). Additionally, they fail to distinguish between slow and fast motoneurones, the latter of which have more C-boutons but are lost earlier in the disease. To circumvent these issues, we quantified the frequency and volume of C-boutons on traced soleus and gastrocnemius motoneurones, representing predominantly slow and fast motor pools respectively. Experiments were performed using the TDP-43{Delta}NLS mouse model that carries a transgenic construct of TDP-43 devoid of its nuclear localization signal, preventing its nuclear import. This results in the emergence of pathological TDP-43 inclusions in the cytoplasm, modelling the main pathology seen in this disorder, accompanied by a severe and lethal ALS phenotype. Our results confirmed changes in both the number and volume of C-boutons with a decrease in number on the more vulnerable, predominantly fast gastrocnemius motoneurones and an increase in number on the less vulnerable, predominantly slow soleus motoneurones. Importantly, these changes were only found in male mice. However, both sexes and motor pools showed a decrease in C-bouton volume. Our experiments confirm that cytoplasmic TDP-43 accumulation is sufficient to drive C-bouton changes.

neuroscience↗