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.

eLife digest

Many people find it easy to follow a conversation while on a busy city street, but this seemingly simple task requires sophisticated processing of sounds. The brain must accurately distinguish speech sounds from background noise, even though the volumes and pitches of those sounds overlap. To make this possible, neurons that process sounds continually adjust the relationship between the volume of a sound and the size of their response. This helps the brain to distinguish more precisely between different sounds, but how this works remains unclear.

Zinc ions form part of almost 3,000 different enzymes and regulatory proteins, and also help neurons to communicate with one another at junctions called synapses. Changes to the amount of zinc ions at the synapses have been seen in disorders including depression and Alzheimer’s disease. By imaging the brains of mice, Anderson, Kumar et al. now show that zinc ions affect how the healthy brain processes sounds.

Treating the mice with a substance that temporarily mops up zinc ions changed how neurons responded to sounds of different volumes. This revealed that zinc ions cause excitatory neurons, which activate neighboring cells, to increase their responses to sounds. Conversely, zinc ions cause inhibitory neurons, which reduce the activity of other cells, to decrease their responses to sounds. The overall effect is to change the balance of excitatory and inhibitory activity in areas of the brain that process sound. Anderson, Kumar et al. propose that these changes make it easier for the brain to process and distinguish different sounds as the environment changes from quiet to loud and vice versa.

As well as revealing a role for zinc ions in normal hearing, these findings may help us to understand disorders such as tinnitus and auditory neuropathies (conditions where the nerve that carries signals from the ear to the brain is damaged, leading to hearing loss). Both tinnitus and auditory neuropathies involve changes in the brain’s ability to increase or decrease its responses to sounds with particular characteristics – processes that may involve the activity of zinc ions.