Euchromatin histone methyltransferase 1 regulates cortical neuronal network development.

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Heterozygous mutations in the Euchromatin histone methyltransferase 1 (EHMT1) gene are linked to Kleefstra syndrome, a neurodevelopmental disorder.
• Kleefstra syndrome presents with autistic-like features and severe intellectual disability (ID), potentially stemming from impaired activity-dependent neural circuit development.
• While EHMT1's role in synaptic and dendritic development is suggested in model organisms, its precise function in human cortical network development remains unclear.

Purpose of the Study:

• To investigate the impact of EHMT1 deficiency on cortical neuronal network activity at both network and single-cell levels.
• To elucidate the role of EHMT1 in the developmental trajectory of neural network function.

Main Methods:

• Utilized micro-electrode arrays (MEAs) for network-level analysis.
• Employed whole-cell patch-clamp recordings for single-cell electrophysiology.
• Examined neural activity patterns during critical developmental transitions.

Main Results:

• EHMT1 deficiency impaired the transition from uncorrelated neuronal firing to synchronized network bursting.
• A transient reduction in spontaneous network bursting and excitatory synaptic currents was observed.
• Miniature excitatory postsynaptic currents remained unaffected, suggesting specific synaptic function alterations.
• Loss of EHMT1 function led to less regular network bursting patterns later in development.

Conclusions:

• EHMT1 deficiency disrupts the normal development of cortical neuronal network activity.
• Impaired network synchrony and altered bursting patterns may contribute to the neurodevelopmental deficits seen in Kleefstra syndrome.
• Temporal misalignment in activity-dependent developmental processes due to EHMT1 loss-of-function is a potential mechanism underlying the syndrome's pathophysiology.