The expression of unconventional vesicular glutamate transporter VGLUT3 by neurons known to release a different classical transmitter has suggested novel roles for signaling by glutamate, but this distribution has raised questions about whether the protein actually contributes to glutamate release. We now report that mice lacking VGLUT3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse in the auditory pathway. The early degeneration of some cochlear ganglion neurons in knockout mice also indicates an important developmental role for the glutamate released by hair cells before the onset of hearing. In addition, the mice exhibit primary, generalized epilepsy that is accompanied by remarkably little change in ongoing motor behavior. The glutamate release conferred by expression of VGLUT3 thus has an essential role in both function and development of the auditory pathway, as well as in the control of cortical excitability.

Summary Sensory processing must be sensitive enough to encode faint signals near the noise floor, but selective enough to differentiate between similar stimuli. Here we describe a layer 6 corticothalamic (L6 CT) circuit in the mouse auditory forebrain that alternately biases sound processing towards hypersensitivity and improved behavioral sound detection or dampened excitability and enhanced sound discrimination. Optogenetic activation of L6 CT neurons could increase or decrease the gain and tuning precision in the thalamus and all layers of the cortical column, depending on the timing between L6 CT activation and sensory stimulation. The direction of neural and perceptual modulation – enhanced detection at the expense of discrimination or vice versa – arose from the interaction of L6 CT neurons and sub-networks of fast-spiking inhibitory neurons that reset the phase of low-frequency cortical oscillations. These findings suggest that L6 CT neurons contribute towards resolving the competing demands of detection and discrimination.

SUMMARY Patterned spontaneous activity is a hallmark of developing sensory systems. In the auditory system, rhythmic bursts of spontaneous activity are generated in cochlear hair cells and propagated along central auditory pathways. The role of these activity patterns in the development of central auditory circuits has remained speculative. Here we demonstrate that blocking efferent cholinergic neurotransmission to developing hair cells in mice that lack the α9 subunit of nicotinic acetylcholine receptors (α9 KO mice) altered the temporal fine-structure of spontaneous activity without changing activity levels. KO mice showed a severe impairment in the functional and structural sharpening of an inhibitory tonotopic map, as evidenced by deficits in synaptic strengthening and silencing of connections and an absence in axonal pruning. These results provide evidence that the precise temporal pattern of spontaneous activity before hearing onset is crucial for the establishment of precise tonotopy, the major organizing principle of central auditory pathways.

A fundamental organizing principle of auditory brain circuits is tonotopy, the orderly representation of the sound frequency to which neurons are most sensitive. Tonotopy arises from the coding of frequency along the cochlea and the topographic organization of auditory pathways. The mechanisms that underlie the establishment of tonotopy are poorly understood. In auditory brainstem pathways, topographic precision is present at very early stages in development, which may suggest that synaptic reorganization contributes little to the construction of precise tonotopic maps. Accumulating evidence from several brainstem nuclei, however, is now changing this view by demonstrating that developing auditory brainstem circuits undergo a marked degree of refinement on both a subcellular and circuit level.Increasing the topographic organization of synaptic connections via activity-dependent refinement is a major milestone in the maturation of neuronal circuits 1 . In the developing auditory system, experience-dependent refinement of tonotopic maps has been well demonstrated in the auditory cortex and in multimodal-integration brain areas [2][3][4][5] . In contrast, primary auditory circuits in the brainstem are assembled with high topographic (tonotopic) precision early in development and show little evidence of subsequent refinement. This picture is based on a wealth of anatomical tracing studies in both birds and mammals that have shown that growing axons innervate their topographically correct target areas from the outset and do not establish aberrant, transient connections to incorrect nuclei [6][7][8][9] . Likewise, physiological studies indicate that a precise tonotopic organization is present as soon as central auditory pathways can be activated by sound [10][11][12] . Even if the formation of a projection is induced by embryonic otocyst (an ectodermal invagination that constitutes the primordium of the internal ear) removal, the projection is tonotopically organized 13 .Recently, however, this traditional picture of a developmentally predetermined and 'hardwired' auditory brainstem has undergone a substantial revision. It is becoming increasingly apparent that auditory synapses in the brainstem can express activity-dependent synaptic plasticity [14][15][16] and that auditory brainstem circuits undergo an unexpected degree of synaptic reorganization. Here we summarize recent evidence from the cochlear nucleus and primary © 2009 Nature America, Inc. All rights reserved.Correspondence should be addressed to K.K. (kkarl@pitt.edu).. (Fig. 1) that support the view that the emergence of precise tonotopy depends on circuit refinement, and discuss potential underlying mechanisms. NIH Public Access Auditory nerve projections to the cochlear nucleusCochlear hair cells, the sensory cells that transform sound energy into electrical signals, are connected to the brain by spiral ganglion neurons whose centrally directed axons form the auditory nerve. After entering the brain, each auditory nerve fiber branches to innervate...