Cell-specific gain modulation by synaptically released zinc in cortical circuits of audition

Abstract

In many excitatory synapses, mobile zinc is found within glutamatergic vesicles and is coreleased with glutamate. Ex vivo studies established that synaptically released (synaptic) zinc inhibits excitatory neurotransmission at lower frequencies of synaptic activity but enhances steady state synaptic responses during higher frequencies of activity. However, it remains unknown how synaptic zinc affects neuronal processing in vivo. Here, we imaged the sound-evoked neuronal activity of the primary auditory cortex in awake mice. We discovered that synaptic zinc enhanced the gain of sound-evoked responses in CaMKII-expressing principal neurons, but it reduced the gain of parvalbumin- and somatostatin-expressing interneurons. This modulation was sound intensity-dependent and, in part, NMDA receptor-independent. By establishing a previously unknown link between synaptic zinc and gain control of auditory cortical processing, our findings advance understanding about cortical synaptic mechanisms and create a new framework for approaching and interpreting the role of the auditory cortex in sound processing.

Synergistic Transcriptional Changes in AMPA and GABAA Receptor Genes Support Compensatory Plasticity Following Unilateral Hearing Loss

“…Acute hearing loss in adulthood shifts the mRNA and protein expression of multiple AMPA and GABAA receptor subunits, as well as other receptor types (Suneja et al, 1998(Suneja et al, , 2000Milbrandt et al, 2000;Holt et al, 2005;Argence et al, 2006;Dong et al, 2010a;Smith et al, 2014) in addition to changes in voltage-gated channels that regulate intrinsic excitability (Yang et al, 2012;Li et al, 2015). Central gain-related changes in postsynaptic receptor densities are likely to vary by neuronal type, such that activity levels across some neural types are stable or suppressed, while others may become increasingly excitable (Takesian et al, 2013;Anderson et al, 2017;Sturm et al, 2017). Here, we used VGLUT and VGAT mRNA to coarsely group neurons into excitatory and inhibitory subclasses (Figure 8), though we did not observe differences between these genetic categories in the STUD condition.…”

Superiority of SpiroZin2 Versus FluoZin-3 for monitoring vesicular Zn2+ allows tracking of lysosomal Zn2+ pools

“…Labile Zn 2+ pools occur in the cytosol, discrete organelles, and within vesicles of secretory cells 5 , and diverse patterns of dynamics have been observed for these pools. In some regions of the brain, for example, presynaptic glutamatergic vesicles co-release glutamate and Zn 2+ into the synaptic cleft during neurotransmission, where it modulates the excitatory post-synaptic current by binding to ion channels ostensibly as part of a gain control mechanism 6 , 7 . Mitochondria in primary rat hippocampal neurons can transiently accumulate Zn 2+ upon treatment with glutamate and Zn 2+ , suggesting that mitochondria may serve as a temporary store of labile Zn 2+ 8 .…”

Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1

“…Zinc is a neuromodulator that regulates glutamatergic, -aminobutyric acid-mediated (GABAergic), and glycinergic synaptic transmission (1-7); short-and long-term synaptic plasticity (2,(8)(9)(10)(11)(12); auditory processing; and acuity for sensory stimulus discrimination (13)(14)(15). The zinc transporter ZnT3 (Slc30a3) packages zinc into presynaptic vesicles of large populations of excitatory neurons in many brain regions, including the cerebral cortex, hippocampus, amygdala, and dorsal cochlear nucleus (DCN) (16).…”