Mapping the emergence of a subcellular balance between excitatory and inhibitory synapses along dendrites

The spatial distribution and organisation of synapses throughout the dendritic arbour is thought to highly influence neuronal activity, including dendritic and somatic firing patterns (Gidon and Segev, 2012; Katz et al, 2009; Liu, 2004; Polsky et al, 2004). However, our understanding of the spatial organisation of excitatory and inhibitory synapses throughout the dendritic arbour is currently incomplete. Previous research in the Burrone lab has identified a balance between the excitatory and inhibitory synapses located throughout the dendritic arbour of murine hippocampal neurons, down to a 5um level (Kemlo, Unpublished). Interestingly, such subcellular excitatory/inhibitory balance was observed in mice at postnatal day 21 (P21), but not P14, suggesting a seven day time window for its development. Additional research has similarly observed a balance between excitatory and inhibitory synapses throughout the dendritic tree of cortical neurons in P41 mice (Lascone et al, 2020). Therefore, it is apparent that a subcellular balance between excitatory and inhibitory synapses throughout the dendritic tree is present in mature murine cortical and hippocampal neurons, yet the details surrounding the development of such organisation is unclear. For example, it may be that such subcellular excitatory/inhibitory balance is activity dependent and thus sensory experience is necessary and/or sufficient for the emergence of the spatial organisation of excitatory and inhibitory synapses throughout the dendritic arbour. It is also possible that there is a critical period for emergence of the subcellular excitatory/inhibitory balance and disruption during this time period may result in an excitatory/inhibitory imbalance, which may subsequently contribute to the development of neurological disorders, such as epilepsy.

Epilepsy is a common neurological condition, affecting around 60 million people worldwide (Epilepsy Society, 2018). Disruption of the excitation/inhibition balance has frequently been reported as the mechanism underlying seizure generation and epileptogensis (Stafstrom, 2014; Bozzi, Provenzano and Casarosa, 2018). Such excitation/inhibition imbalance can result in the over-excitation of neurons, causing periods of abnormal electrical discharge, otherwise known as seizures. Interestingly, previous research has demonstrated that mutations in the gene encoding Teneurin-3, TENM-3, provide a resistance against seizure induction (Hortopan, Dinday and Baraban, 2010). Teneurin-3 is a cell adhesion molecule (Jackson et al, 2018), which is crucial for synaptic formation and organisation (Mosca, 2015). It is possible that TENM-3 mutations disrupt the excitation/inhibition balance at a subcellular level to increase inhibition, thus an epileptic-like phenotype of over-excitation (in terms of neuronal activity) is less likely. Moreover, previous research has observed that teneurins contribute to the specificity of synapse formation, through interactions with latrophillins (an adhesion G protein-coupled receptor; Sando, Jiang and Sudof, 2019) and that Teneurin-3 may orchestrate complex circuit assembly in the mammalian brain (Berns et al, 2018). However, it is currently not known if Tenm-3 mutations lead to a subcellular excitation/inhibition imbalance and consequently to an atypical spatial distribution of synapses throughout the dendritic arbour. Further research is thus required to assess the subcellular excitation/inhibition balance in Tenm-3 mutant models.