Hyaluronan regulates synapse formation and function in developing neural networks

Wilson E, Knudson W, and Newell-Litwa K.

Scientific Reports, 2020



Neurodevelopment disorders often present with an increase in excitability of neurons, for example epilepsy and autism; and could be due to a synaptic alteration that disrupts the balance between excitatory and inhibitory signaling.   The authors seek to investigate the role of the extracellular matrix in directing synapse formation and regulation of synaptic function in human cortical brain development.  Hyaluronan compromises part of the extracellular matrix and the authors investigated how acute perturbation of levels impacted the development of synaptogenesis during development and therefore the resulting neuronal activity.  In order to test the effect, 3-D cortical spheroids were derived from hiPSCs.  The results showed that an decrease in hyaluronan resulted in an increase of excitatory synapse formation and corresponding increase in excitatory network activity.  In contrast, a the addition of hyaluronan resulted in a decrease in excitatory synapse formation.  


Recording neural network activity:

76 day old cortical organoids were dissociated and plated in multielectrode array (MEA) plates and allowed to acclimated for two weeks before recording and treatment.  TTX treatment was used to verify recordings were du to spontaneous neural activity. 

Given the observed changes in neuron synapse formation with the increase or decrease in hyaluronan concentration, the authors hypothesized there would be an observable change in neuronal activity.  

After two weeks in culture, the dissociated cortical spheroid neurons re-established connections and baseline activity was recorded.  The HA manipulation treatment was then applied and corresponding spontaneous action potentials recorded for 24 hours.  Results showed a significant increase in neural activity, including network bursts, with the HA removal over untreated cultures.  Conversely the addition of HA had a decrease in neural activity compared to untreated cells.  Both mean spiking rate and network bursting were evaluated.  Overall this suggested the HA prevents hyperexcitable states during development.