Fine Control of Sound Frequency Tuning and Frequency Discrimination Acuity by Synaptic Zinc Signaling in Mouse Auditory Cortex

Abstract

Neurons in the auditory cortex are tuned to specific ranges of sound frequencies. Although the cellular and network mechanisms underlying neuronal sound frequency selectivity are well studied and reflect the interplay of thalamocortical and intracortical excitatory inputs and further refinement by cortical inhibition, the precise synaptic signaling mechanisms remain less understood. To gain further understanding on these mechanisms and their effects on sound-driven behavior, we used in vivo imaging as well as behavioral approaches in awake and behaving female and male mice. We discovered that synaptic zinc, a modulator of neurotransmission and responsiveness to sound, sharpened the sound frequency tuning of principal and parvalbumin-expressing neurons and widened the sound frequency tuning of somatostatin-expressing inhibitory neurons in layer 2/3 of the primary auditory cortex. In the absence of cortical synaptic zinc, mice exhibited reduced acuity for detecting changes in sound frequencies. Together, our results reveal that cell-type-specific effects of zinc contribute to cortical sound frequency tuning and enhance acuity for sound frequency discrimination.

Mechanisms Underlying Long-Term Synaptic Zinc Plasticity at Mouse Dorsal Cochlear Nucleus Glutamatergic Synapses

“…In the auditory cortex of awake mice, synaptic zinc enhances the responsiveness (gain) of principal neurons to sound, reduces the gain of interneurons (Anderson et al, 2017), sharpens the sound frequency tuning of principal neurons (Kumar et al, 2019;Kouvaros et al, 2020), and enhances frequency discrimination acuity (Kumar et al, 2019). In the somatosensory cortex, synaptic zinc signaling contributes to whisker-mediated fine texture discrimination (Patrick Wu and Dyck, 2018).…”

Effects of enriched housing on the neuronal morphology of mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

“…The general lack of morphological abnormalities identified in ZnT3 KO mice is not entirely surprising, considering that these mice exhibit no pronounced behavioural phenotype (Cole et al, 2001; but see Yoo et al, 2016) but instead show mild abnormalities or deficiencies across several behavioural domains (Martel et al, 2010(Martel et al, , 2011Sindreu et al, 2011;Thackray et al, 2017;Wu & Dyck, 2018, Kumar et al, 2019. This suggests that most behavioural abnormalities in these mice are mediated not by gross changes in neuronal morphology, but by changes on a smaller scale at the level of neurotransmission, which vesicular zinc has been shown to modulate through its effects on several different receptors (Perez-Rosello et al, 2013;Anderson et al, 2015;Kalappa et al, 2015).…”

“…To speculate, it is possible that an aberrant increase in dendritic length could result in a reduction in the specificity of the sensory input received by pyramidal neurons in barrel cortex, contributing to an impairment in discriminating between fine differences in texture. In addition to following up on this possibility, it would be interesting to examine whether our observation of abnormal morphology in barrel cortex neurons extends to other sensory areas such as auditory cortex, especially given that ZnT3 KO mice also exhibit deficits in auditory frequency discrimination (Kumar et al, 2019).…”

“…Accordingly, these ZnT3 knockout (KO) mice show a complete lack of vesicular zinc (Cole et al, 1999;Linkous et al, 2008). While this does not appear to cause gross behavioural abnormalities (Cole et al, 2001; but see Yoo et al, 2016), it does affect several functions, including fear memory (Martel et al, 2010(Martel et al, , 2011, object recognition memory (Martel et al, 2011), contextual discrimination (Sindreu et al, 2011), skilled motor learning (Thackray et al, 2017), and both texture and auditory frequency discrimination (Wu & Dyck, 2018;Kumar et al, 2019).…”

Synaptic Zn2+potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior

“…ZnT3 knockout (KO) mice lack the ability to package Zn 2+ into these vesicles and consequently lack synaptic Zn 2+ release (9, 10). ZnT3 KO mice are viable, fertile, and do not show major behavioral abnormalities across spatial learning, memory, or sensorimotor tasks, though they do exhibit small deficits in skilled reaching tasks (11, 12), fear learning (13), and sensory deficits (14, 15).…”