Modulation of Hyperpolarization-Activated Inward Current and Thalamic Activity Modes by Different Cyclic Nucleotides

Area of Science:

• Neuroscience
• Molecular Biology
• Computational Neuroscience

Background:

• The hyperpolarization-activated current (I_h) is crucial for rhythmic activity in thalamocortical (TC) neurons.
• Cyclic adenosine monophosphate (cAMP) facilitates I_h by modulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
• The role of cyclic guanosine monophosphate (cGMP) in I_h modulation remains unclear.

Purpose of the Study:

• To investigate the role of nitric oxide-sensitive guanylyl cyclase 2 (NO-GC2) in modulating thalamic I_h.
• To analyze the voltage-dependency and cGMP/cAMP-sensitivity of I_h in TC neurons.
• To understand the impact of NO-GC2 deficiency on neural activity and network oscillations.

Main Methods:

• Whole-cell voltage clamp recordings in dorsal lateral geniculate nucleus (dLGN) TC neurons from wild-type (WT) and NO-GC2-deficient (NO-GC2^-/-) mice.
• Application of cyclic nucleotide analogs (8-Br-cAMP/8-Br-cGMP) and cyclase inhibitors (SQ22536, ODQ).
• Current clamp recordings, mathematical modeling of thalamic networks, and cortical local field potential (LFP) recordings in freely behaving mice.

Main Results:

• NO-GC2^-/- TC neurons exhibited a hyperpolarized I_h activation curve (V_1/2) compared to WT.
• cGMP and cAMP dose-dependently shifted V_1/2 to positive values in both genotypes.
• NO-GC2 deficiency reduced I_h-dependent voltage sag, action potential firing, and intrathalamic rhythmic bursting.
• Enhanced delta and theta band activity during active wakefulness and REM sleep in NO-GC2^-/- mice.

Conclusions:

• cGMP facilitates I_h activation, contributing to tonic activity in TC neurons.
• Basal cGMP production supports fast rhythmic activity in the cortex.
• NO-GC2 plays a significant role in regulating thalamic I_h and associated network oscillations, influencing sleep patterns.