δ subunit-containing GABA_A IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• GABA_A receptors are crucial for central nervous system neurotransmission.
• Receptors typically contain either a δ or a γ2 subunit, mediating different inhibitory postsynaptic currents (IPSCs).
• The precise mechanisms underlying the slower decay of δ IPSCs compared to γ2 IPSCs remain unclear.

Purpose of the Study:

• To re-examine the distinct roles of δ and γ2 subunit-containing GABA_A receptors.
• To investigate the contribution of transmitter diffusion versus channel kinetics in δ IPSC decay.
• To understand the functional relationship between these two major GABA_A receptor populations.

Main Methods:

• Utilized gene editing to confer picrotoxin resistance specifically to δ GABA_A receptors in mice.
• Employed pharmacological isolation to study δ receptors in mouse dentate granule cells.
• Applied varying concentrations of GABA to nucleated patches and manipulated GABA diffusion using dextran.

Main Results:

• δ and γ2 IPSCs were modulated similarly by presynaptic changes and GABA lifetime, indicating proportional recruitment.
• δ IPSCs exhibited greater sensitivity to altered GABA release and rapid antagonists, suggesting a spillover contribution.
• Spontaneous δ IPSCs were mainly driven by channel deactivation, with local GABA actions for both receptor types.
• Evoked δ IPSCs were affected by reduced GABA diffusion, while spontaneous IPSCs were not.

Conclusions:

• δ GABA_A receptors are activated by both synaptic and diffusional GABA.
• Channel deactivation, rather than diffusion, is the primary driver of spontaneous δ IPSCs.
• A functional parallel exists between δ/γ2 GABA_A receptors and NMDA/AMPA glutamate receptors.