Developmental effect of RASopathy mutations on neuronal network activity on a chip

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• RASopathies are genetic disorders caused by RAS/MAPK pathway overactivation.
• Clinical manifestations include neurocognitive impairments, but underlying neuronal mechanisms are unclear.

Purpose of the Study:

• Investigate the effect of RASopathy mutations on neuronal network establishment and maturation.
• Determine neuron-specific cellular and network phenotypes associated with RASopathy.

Main Methods:

• Cultured cortical neurons from RASopathy mouse models (Ptpn11 D61Y, Kras V14l).
• Performed longitudinal multielectrode array recordings of spontaneous and evoked neuronal activity.
• Developed custom MATLAB tools for data analysis.

Main Results:

• Identified a convergent developmental phenotype in neurons with RASopathy mutations, more pronounced early on.
• Observed fading of the phenotype over time, suggesting compensatory mechanisms.
• Detected persistent alterations in excitatory/inhibitory balance and network excitability in mature networks.

Conclusions:

• RASopathy mutations affect neuronal network development and maturation.
• Compensatory mechanisms may mitigate early-stage deficits, but long-term network excitability is altered.
• Provides insights into the link between genetic mutations and neurocognitive deficits in RASopathies.