Nicotinic acetylcholine receptor subunit α₇-knockout mice exhibit degraded auditory temporal processing

Abstract

The CHRNA7 gene that encodes the α7-subunit of the nicotinic acetylcholine receptor (α7-nAChR) has been associated with some autism spectrum disorders and other neurodevelopmental conditions characterized, in part, by auditory and language impairment. These conditions may include auditory processing disorders that represent impaired timing of neural activity, often accompanied by problems understanding speech. Here, we measure timing properties of sound-evoked activity via the auditory brainstem response (ABR) of α7-nAChR knockout mice of both sexes and wild-type colony controls. We find a significant timing delay in evoked ABR signals that represents midbrain activity in knockouts. We also examine spike-timing properties of neurons in the inferior colliculus, a midbrain nucleus that exhibits high levels of α7-nAChR during development. We find delays of evoked responses along with degraded spiking precision in knockout animals. We find similar timing deficits in responses of neurons in the superior paraolivary nucleus and ventral nucleus of the lateral lemniscus, which are brainstem nuclei thought to shape temporal precision in the midbrain. In addition, we find that other measures of temporal acuity including forward masking and gap detection are impaired for knockout animals. We conclude that altered temporal processing at the level of the brainstem in α7-nAChR-deficient mice may contribute to degraded spike timing in the midbrain, which may underlie the observed timing delay in the ABR signals. Our findings are consistent with a role for the α7-nAChR in types of neurodevelopmental and auditory processing disorders and we identify potential neural targets for intervention. NEW & NOTEWORTHY Disrupted signaling via the α7-nicotinic acetylcholine receptor (α7-nAChR) is associated with neurodevelopmental disorders that include impaired auditory processing. The underlying causes of dysfunction are not known but a common feature is abnormal timing of neural activity. We examined temporal processing of α7-nAChR knockout mice and wild-type controls. We found degraded spike timing of neurons in knockout animals, which manifests at the level of the auditory brainstem and midbrain.

Cholinergic Projections From the Pedunculopontine Tegmental Nucleus Contact Excitatory and Inhibitory Neurons in the Inferior Colliculus

“…Application of ACh to the IC affects the responses to auditory stimuli of a majority of IC neurons (Watanabe and Simada, 1973 ; Farley et al, 1983 ; Habbicht and Vater, 1996 ). Such effects can modify temporal processing and forward masking (Felix et al, 2019 ). Supporting the idea of widespread effects of ACh in the IC, both nicotinic and muscarinic ACh receptors are present throughout the IC, as is acetylcholinesterase, the enzyme that degrades ACh (Shute and Lewis, 1967 ; Cortes et al, 1984 ; Glendenning and Baker, 1988 ; Henderson and Sherriff, 1991 ; Happe and Morley, 2004 ).…”

“…Staining for β4 nicotinic cholinergic receptor subunits is heaviest in layer 2 of the IClc, with moderate expression in the ICc and less in the ICd (Gahring et al, 2004 ). These receptors have recently been reported to aid in the modulation of spike timing and forward masking in the IC (Felix et al, 2019 ). The IClc has also been noted for its comparatively high levels of the α7 nicotinic receptor subunit and high levels of acetylcholinesterase (Happe and Morley, 2004 ; Dillingham et al, 2017 ).…”

α3β4* Nicotinic acetylcholine receptors strongly modulate the excitability of VIP neurons in the mouse inferior colliculus

“…Consistent with this, in vivo studies have shown that nicotinic drugs alter the gain of input-output functions in IC neurons (Farley et al, 1983;Habbicht & Vater, 1996), and human psychophysics studies indicate that nicotine improves performance in auditory attention and discrimination tasks (Knott et al, 2012;Smucny et al, 2016;Pham et al, 2020), an effect partly attributable to alterations in the IC (Askew et al, 2017). In addition, temporal coding of auditory stimuli is degraded in the IC of α7 knockout mice (Felix et al, 2019). However, despite the importance of nAChRs to auditory processing, the cellular mechanisms by which nAChRs influence the excitability IC neurons remain largely unknown.…”

“…Growing evidence indicates that cholinergic signaling through nicotinic acetylcholine receptors (nAChRs) critically shapes sound processing in the central auditory system (Goyer et al, 2016;Askew et al, 2017;Felix et al, 2019;Zhang et al, 2021). The inferior colliculus (IC), the midbrain hub of the central auditory system, receives extensive input from cholinergic neurons in the pontomesencephalic tegmentum (PMT; , and expresses several nAChR subunits, including α3, α4, α7, β2, β3, and β4 (Clarke et al, 1985;Wada et al, 1989;Morley & Happe, 2000;Whiteaker et al, 2002;Salas et al, 2003;Gahring et al, 2004;Happe & Morley, 2004;Bieszczad et al, 2012;Sottile et al, 2017).…”

Multiple Sources of Cholinergic Input to the Superior Olivary Complex

“…Receptor binding indicates that SOC nuclei have high levels of cholinergic receptors (Morley and Happe, 2000;Gahring et al, 2004;Happe and Morley, 2004). Developmental knock-out of alpha-7 nicotinic receptors suggests that ACh may contribute to temporal processing in the superior paraolivary nucleus (Felix et al, 2019). We have shown previously that, in the MNTB, ACh affects suprathreshold response magnitude, enhances near-threshold level discrimination, and enhances coding for signal in noise (Zhang et al, 2021).…”