Abstract
The hyperpolarization-activated inward current, Ih, plays a key role in the generation of rhythmic activities in thalamocortical (TC) relay neurons. Cyclic nucleotides, like 3′,5′-cyclic adenosine monophosphate (cAMP), facilitate voltage-dependent activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels by shifting the activation curve of Ih to more positive values and thereby terminating the rhythmic burst activity. The role of 3′,5′-cyclic guanosine monophosphate (cGMP) in modulation of Ih is not well understood. To determine the possible role of the nitric oxide (NO)-sensitive cGMP-forming guanylyl cyclase 2 (NO-GC2) in controlling the thalamic Ih, the voltage-dependency and cGMP/cAMP-sensitivity of Ih was analyzed in TC neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in wild type (WT) and NO-GC2-deficit (NO-GC2−/−) mice. Whole cell voltage clamp recordings in brain slices revealed a more hyperpolarized half maximal activation (V1/2) of Ih in NO-GC2−/− TC neurons compared to WT. Different concentrations of 8-Br-cAMP/8-Br-cGMP induced dose-dependent positive shifts of V1/2 in both strains. Treatment of WT slices with lyase enzyme (adenylyl and guanylyl cyclases) inhibitors (SQ22536 and ODQ) resulted in further hyperpolarized V1/2. Under current clamp conditions NO-GC2−/− neurons exhibited a reduction in the Ih-dependent voltage sag and reduced action potential firing with hyperpolarizing and depolarizing current steps, respectively. Intrathalamic rhythmic bursting activity in brain slices and in a simplified mathematical model of the thalamic network was reduced in the absence of NO-GC2. In freely behaving NO-GC2−/− mice, delta and theta band activity was enhanced during active wakefulness (AW) as well as rapid eye movement (REM) sleep in cortical local field potential (LFP) in comparison to WT. These findings indicate that cGMP facilitates Ih activation and contributes to a tonic activity in TC neurons. On the network level basal cGMP production supports fast rhythmic activity in the cortex.
Highlights
MATERIALS AND METHODSCyclic nucleotides, like cyclic adenosine monophosphate and cyclic guanosine monophosphate bind to the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and stabilize their open state (Zagotta et al, 2003)
Thalamic hyperpolarization activated current (Ih) properties were analyzed in wild type (WT) and nitric oxide (NO)-GC2−/− mice (Figure 1A)
Analyses of activating and deactivating currents revealed that the loss of NO-GC2 was associated with a significant negative shift in voltage-dependency of activation (WT: half maximal activation (V1/2) = −86.4 ± 0.9 mV, n = 11; NO-GC2−/−: V1/2 = −91.8 ± 1.1 mV, n = 13; P < 0.05; Figures 1B,C), whereas current density remained unaltered (WT: Ih = 6.1 ± 0.6 pA/pF, n = 11; NO-GC2−/−: Ih = 6.4 ± 0.8 pA/pF, n = 13; P > 0.05; Figure 1D)
Summary
MATERIALS AND METHODSCyclic nucleotides, like cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) bind to the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and stabilize their open state (Zagotta et al, 2003). To determine the functional impact of NO-GC2 activity on passive membrane properties and neuronal firing, TC neurons were recorded under current clamp conditions from the RMP (Figure 4A).
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