Original Research / Publications

Homeostatic Control of Spontaneous Activity in the Developing Auditory System.

Neurons in the developing auditory system exhibit spontaneous bursts of activity before hearing onset. How this intrinsically generated activity influences development remains uncertain, because few mechanistic studies have been performed in vivo. We show using macroscopic calcium imaging in unanesthetized mice that neurons responsible for processing similar frequencies of sound exhibit highly synchronized activity throughout the auditory system during this critical phase of development. Spontaneous activity normally requires synaptic excitation of spiral ganglion neurons (SGNs). Unexpectedly, tonotopic spontaneous activity was preserved in a mouse model of deafness in which glutamate release from hair cells is abolished. SGNs in these mice exhibited enhanced excitability, enabling direct neuronal excitation by supporting cell-induced potassium transients. These results indicate that homeostatic mechanisms maintain spontaneous activity in the pre-hearing period, with significant implications for both circuit development and therapeutic approaches aimed at treating congenital forms of deafness arising through mutations in key sensory transduction components.

Original Research / Publications

NMDA Receptors Enhance Spontaneous Activity and Promote Neuronal Survival in the Developing Cochlea.

Spontaneous bursts of activity in developing sensory pathways promote maturation of neurons, refinement of neuronal connections, and assembly of appropriate functional networks. In the developing auditory system, inner hair cells (IHCs) spontaneously fire Ca(2+) spikes, each of which is transformed into a mini-burst of action potentials in spiral ganglion neurons (SGNs). Here we show that NMDARs are expressed in SGN dendritic terminals and play a critical role during transmission of activity from IHCs to SGNs before hearing onset. NMDAR activation enhances glutamate-mediated Ca(2+) influx at dendritic terminals, promotes repetitive firing of individual SGNs in response to each synaptic event, and enhances coincident activity of neighboring SGNs that will eventually encode similar frequencies of sound. Loss of NMDAR signaling from SGNs reduced their survival both in vivo and in vitro, revealing that spontaneous activity in the prehearing cochlea promotes maturation of auditory circuitry through periodic activation of NMDARs in SGNs.

Original Research / Publications

Spontaneous Activity of Cochlear Hair Cells Triggered by Fluid Secretion Mechanism in Adjacent Support Cells.

Spontaneous electrical activity of neurons in developing sensory systems promotes their maturation and proper connectivity. In the auditory system, spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from glia-like inner supporting cells (ISCs), facilitating maturation of central pathways before hearing onset. Here, we find that ATP stimulates purinergic autoreceptors in ISCs, triggering Cl(-) efflux and osmotic cell shrinkage by opening TMEM16A Ca(2+)-activated Cl(-) channels. Release of Cl(-) from ISCs also forces K(+) efflux, causing transient depolarization of IHCs near ATP release sites. Genetic deletion of TMEM16A markedly reduces the spontaneous activity of IHCs and spiral ganglion neurons in the developing cochlea and prevents ATP-dependent shrinkage of supporting cells. These results indicate that supporting cells in the developing cochlea have adapted a pathway used for fluid secretion in other organs to induce periodic excitation of hair cells.

Original Research / Publications

Spontaneous activity in the developing auditory system.

Spontaneous electrical activity is a common feature of sensory systems during early development. This sensory-independent neuronal activity has been implicated in promoting their survival and maturation, as well as growth and refinement of their projections to yield circuits that can rapidly extract information about the external world. Periodic bursts of action potentials occur in auditory neurons of mammals before hearing onset. This activity is induced by inner hair cells (IHCs) within the developing cochlea, which establish functional connections with spiral ganglion neurons (SGNs) several weeks before they are capable of detecting external sounds. During this pre-hearing period, IHCs fire periodic bursts of Ca(2+) action potentials that excite SGNs, triggering brief but intense periods of activity that pass through auditory centers of the brain. Although spontaneous activity requires input from IHCs, there is ongoing debate about whether IHCs are intrinsically active and their firing periodically interrupted by external inhibitory input (IHC-inhibition model), or are intrinsically silent and their firing periodically promoted by an external excitatory stimulus (IHC-excitation model). There is accumulating evidence that inner supporting cells in Kölliker’s organ spontaneously release ATP during this time, which can induce bursts of Ca(2+) spikes in IHCs that recapitulate many features of auditory neuron activity observed in vivo. Nevertheless, the role of supporting cells in this process remains to be established in vivo. A greater understanding of the molecular mechanisms responsible for generating IHC activity in the developing cochlea will help reveal how these events contribute to the maturation of nascent auditory circuits.

Original Research / Publications

The origin of spontaneous activity in the developing auditory system.

Spontaneous activity in the developing auditory system is required for neuronal survival as well as the refinement and maintenance of tonotopic maps in the brain. However, the mechanisms responsible for initiating auditory nerve firing in the absence of sound have not been determined. Here we show that supporting cells in the developing rat cochlea spontaneously release ATP, which causes nearby inner hair cells to depolarize and release glutamate, triggering discrete bursts of action potentials in primary auditory neurons. This endogenous, ATP-mediated signalling synchronizes the output of neighbouring inner hair cells, which may help refine tonotopic maps in the brain. Spontaneous ATP-dependent signalling rapidly subsides after the onset of hearing, thereby preventing this experience-independent activity from interfering with accurate encoding of sound. These data indicate that supporting cells in the organ of Corti initiate electrical activity in auditory nerves before hearing, pointing to an essential role for peripheral, non-sensory cells in the development of central auditory pathways.