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

突触在树突中的空间分布和组织被认为高度影响神经元的活动，包括树突和躯体的放电模式(Gidon和Segev，2012；Katz等人，2009；Liu，2004；Polsky等人，2004)。然而，我们对树突中兴奋性和抑制性突触的空间组织的了解目前还不完全。Burrone实验室之前的研究已经确定了分布在小鼠海马神经元树突上的兴奋性和抑制性突触之间的平衡，低至5微米(Kemlo，未发表)。有趣的是，这种亚细胞兴奋/抑制平衡在小鼠出生后第21天(P21)就观察到了，但在P14天没有观察到，这表明它的发育有7天的时间窗口。其他研究也同样观察到了P41小鼠皮质神经元树状突触中兴奋性和抑制性突触之间的平衡(Lascon等人，2020年)。因此，很明显，在成熟的小鼠皮质和海马神经元中，整个树状突触的兴奋性和抑制性突触之间存在亚细胞平衡，但围绕这种组织发育的细节尚不清楚。例如，这种亚细胞兴奋性/抑制性平衡可能是活动依赖的，因此感觉经验对于整个树突中兴奋性和抑制性突触的空间组织的出现是必要的和/或充分的。亚细胞兴奋性/抑制性平衡的出现也可能有一个关键期，在此期间的破坏可能导致兴奋性/抑制性失衡，这可能随后导致神经功能障碍的发展，如癫痫。癫痫是一种常见的神经疾病，全世界约有6000万人受到影响(癫痫协会，2018年)。兴奋/抑制平衡的破坏经常被报告为癫痫发生和癫痫发生的机制(Stafstrom，2014；Bozzi，Provenzano和Casarosa，2018)。这种兴奋/抑制失衡会导致神经元过度兴奋，导致异常放电的周期，也称为癫痫发作。有趣的是，先前的研究已经证明，编码Teneurin-3，TENM-3的基因突变提供了对癫痫诱导的抵抗(Hortopan，Dinday和Baraban，2010)。Teneurin-3是一种细胞黏附分子(Jackson等人，2018)，它对突触的形成和组织至关重要(Mosca，2015)。TENM-3突变可能会在亚细胞水平上破坏兴奋/抑制平衡以增加抑制，因此不太可能出现癫痫样的过度兴奋表型(就神经元活动而言)。此外，先前的研究已经观察到，Teneurin通过与Latrophillins(一种粘附性G蛋白偶联受体，Sando，酱和Souof，2019)相互作用，有助于突触形成的特异性，并且Teneurin-3可能在哺乳动物的大脑中协调复杂的电路组装(Berns等，2018年)。然而，目前尚不清楚Tenm-3基因突变是否导致亚细胞兴奋/抑制失衡，从而导致突触在树突丛中的非典型空间分布。因此，需要进一步的研究来评估Tenm-3突变模型中的亚细胞兴奋/抑制平衡。

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inhibitory synapses located throughout the dendritic arbour of murine hippocampal neurons, down to a 5um level (Kemlo, Unpublished).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.