α_1A‐Adrenergic regulation of inhibition in the olfactory bulb

Abstract

Key points• Here, in mouse brain slices, we examined the cellular effects of noradrenaline to better understand its influence on olfactory bulb processing.• β-and α 1 -adrenergic receptor activation increases GABA currents in mitral cells in an age-dependent manner; the β-adrenergic effect is prominent only during early postnatal weeks, while the α 1 effect is present at all ages.• This study focused on the α 1 -mediated increase in GABA inhibitory currents in mitral cells and found noradrenaline acts on the α 1A -adrenergic receptor subtype to produce long-lasting excitation of granule cells.• The enhancement of inhibition by noradrenaline was consistent across a broad concentration range; at all concentrations, noradrenaline increased inhibitory currents in mitral cells.• Our studies highlight the important role of α 1A -adrenergic receptor subtypes in increasing inhibition at dendrodendritic synapses, suggesting a synaptic mechanism for noradrenergic modulation of olfactory driven behaviours.Abstract By regulating inhibition at dendrodendritic synapses between mitral and granule cells (GCs), noradrenergic neurons extending from the brainstem provide an input essential for odour processing in the olfactory bulb (OB). In the accessory OB (AOB), we have recently shown that noradrenaline (NA) increases GABA inhibitory input on to mitral cells (MCs) by exciting GCs. Here, we show that GCs in the main OB (MOB) exhibit a similar response to NA, indicating a common mechanism for noradrenergic regulation of GC→MC inhibition throughout the OB. In GCs of the MOB, NA (10 μM) produced a robust excitatory effect that included a slow afterdepolarization that followed a train of action potentials evoked by a current stimulus. The depolarization and slow afterdepolarization in GCs were blocked by the α 1A -adrenergic receptor (AR) selective antagonist WB 4101 (30 nM) and mimicked by the α 1A -AR selective agonist A 61603 (1 μM). In recordings from MCs, A 61603 (30 nM-1 μM) produced a sizeable increase in the frequency of spontaneous and miniature IPSCs, an effect completely abolished by the GABA A receptor antagonist gabazine (5 μM). Likewise, activation of β-ARs increased the frequency of spontaneous IPSCs; however, this effect was smaller and confined to the first postnatal weeks. NA enhanced inhibition in MCs across a broad concentration range (0.1-30 μM) and its effects were completely abolished by a mixture of α 1 -and β-AR antagonists (1 μM prazosin and 10 μM propranolol). Furthermore, the general α 2 -AR agonist clonidine (10 μM) failed to affect sIPSC frequency. Thus, the NA-mediated increase in GC→MC inhibition in the OB results mostly from activation of the α 1A -AR subtype.

Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells

“…These results are generally consistent with experimental data drawn from rats (Nai et al 2010), in which neither ADPs nor persistent firing were reported under NE modulation. However, interestingly, in analogous studies performed in mouse OB slices, a submaximal concentration of NE application (10.0 M) did produce a slow ADP (in addition to direct membrane depolarization) that could lead to quasipersistent firing, even when starting from more hyperpolarized resting membrane potentials than evoke ADPs under CCh modulation (i.e., Ϫ60 mV; Zimnik et al 2013).…”

“…Specifically, our base model expresses strong frequency adaptation and large AHPs, replicating experimental data drawn from rat main OB slices (Nai et al 2010;Pressler et al 2007) and evincing relatively large I M and I AHP conductances. In contrast, the mouse main OB GCs studied by Zimnik et al (2013) exhibit much smaller AHP responses (1 mV AHP from a 500-ms depolarization; Figs. 1C and 3A from Zimnik et al 2013), indicating that they express far smaller I M and I AHP conductances.…”

“…In contrast, the mouse main OB GCs studied by Zimnik et al (2013) exhibit much smaller AHP responses (1 mV AHP from a 500-ms depolarization; Figs. 1C and 3A from Zimnik et al 2013), indicating that they express far smaller I M and I AHP conductances. Indeed, after we blocked the slow AHP in the GC model cell by reducing the I M and I AHP conductances from 0.23 mS/cm 2 to 0.03 mS/cm 2 ( Fig.…”

“…The net result appears to be an enhancement of neuronal SNRs and improved detection of very-low-concentration odorants (Escanilla et al 2010). Activation of ␤-receptors does not appear to significantly modulate GC activity in adult mice (Zimnik et al 2013).…”

“…Because ␣2-receptors have a higher affinity for NE than ␣1-receptors, ␣2-receptor effects dominate at very low concentrations of NE (Nai et al 2009(Nai et al , 2010. With increasing concentrations of NE, ␣1-receptor effects come to dominate the ␣2-mediated effects in GCs, increasing their inhibition of MCs while also directly depolarizing MCs (Hayar et al 2001;Nai et al 2009;Zimnik et al 2013). The net result appears to be an enhancement of neuronal SNRs and improved detection of very-low-concentration odorants (Escanilla et al 2010).…”