Abnormal Neuronal Excitability and Reduced Parvalbumin Expression in Shank3-Deficient Parvalbumin Neurons of the...

Area of Science:

• Neuroscience
• Cellular Biology
• Neuropsychiatry

Background:

• Fast-spiking inhibitory neurons in the thalamic reticular nucleus (TRN) regulate thalamocortical communication.
• Parvalbumin (PV) neurons are crucial for calcium buffering, and their dysfunction is implicated in neuropsychiatric disorders.
• SHANK3 deficiency is linked to autism spectrum disorders (ASD), but cellular mechanisms remain unclear.

Purpose of the Study:

• Investigate the role of SHANK3 in TRN PV neuron function.
• Determine the impact of SHANK3 deficiency on neuronal excitability and calcium dynamics.
• Explore the link between SHANK3, PV expression, and calcium buffering in neuropsychiatric disorders.

Main Methods:

• Electrophysiological recordings in Shank3-/- mice.
• Analysis of parvalbumin (PV) expression and dendritic calcium transients.
• Experimental manipulation of calcium-buffering capacity using EGTA.

Main Results:

• Shank3-/- mice exhibited increased burst firing and decreased tonic firing in TRN PV neurons.
• Reduced PV expression and impaired calcium-buffering capacity were observed in Shank3-/- PV neurons.
• Supplementation with EGTA normalized action potential firing in Shank3-/- PV neurons.
• Similar alterations were found in HCN2-/- mice, suggesting a conserved pathway.

Conclusions:

• SHANK3 deficiency leads to impaired calcium buffering and altered neuronal excitability in TRN PV neurons.
• Reduced PV expression is a key factor in the observed cellular dysfunction.
• This pathway represents a potential pathological basis for ASD and other neuropsychiatric disorders.