Dan H. Sanes

Development and plasticity of the auditory system

The sound environment has a profound influence on the maturation of growth and physiology of central auditory connections. Perhaps the most devastating example of this effect occurs following neonatal deafness. Most studies of developmental plasticity focus on the cellular mechanisms that operate at excitatory synapses, while little is known about the maturation of inhibitory synaptic contacts. For example, how are the number and location of inhibitory synapses regulated during development? Does this process depend on auditory experience and synaptic activity? Are inhibitory synapses effected by hearing loss? To answer these questions, I began to study the inhibitory projections from a glycinergic nucleus in the auditory brain stem, called the medial nucleus of trapezoid body (MNTB), cleverly named to ward off further investigation.

MNTB neurons project a short distance to a target population called the lateral superior olive (LSO). This inhibitory projection is activated by the contralateral ear, while LSO neurons receive excitatory connections from the ipsilateral ear.

In our early studies, we found that decreased inhibitory transmission prevented MNTB arbors from attaining their normal specificity - they remained more spread out along the tonotopic axis of LSO. Surprisingly, inhibitory transmission also influences the development of excitatory connections within LSO: when inhibitory transmission is decreased, the excitatory synapses become stronger. Since the primary duty of this simple circuit is to integrate excitatory and inhibitory transmission, and to encode the location of sound along the horizon, it seems reasonable that the strength of these two pathways should reach a balanced state during the course of development. Our experimental findings suggest that synaptic activity contributes to creating this balance.

What are the developmental mechanisms that allow for the adjustment of inhibitory synaptic strength? We recently discovered that inhibitory synapses in the LSO undergo activity-dependent long-term depression (LTD). This mechanism is age-dependent, and is most prominent during the time when MNTB arbors are becoming refined in LSO. The signaling pathways that underlie inhibitory synaptic plasticity are now becoming clear: As it turns out, our glycinergic projection to LSO also releases GABA during early development! This GABA signaling appears to be important for synaptic plasticity because a specific GABA_B receptor antagonist blocks inhibitory LTD. Furthermore, the induction and maintenance of inhibitory depression occurs postsynaptically: direct application of GABA, but not glycine, to the LSO neuron is sufficient to produce depression

We have extended our studies of inhibitory synapses to consider how they are affected by deafness during early development. Within 24 hours of hearing loss, inhibitory synapses within the auditory midbrain have become extremely weak, and this is due to a huge depolarization of the inhibitory synaptic reversal potential. Interestingly, the excitatory synapses are not weakened by deafness, leading to a dramatic imbalance between inhibition and excitation.

With these two models of plasticity in mind, we have begun to explore how inhibitory synapses in the auditory cortex mature and how they respond to environmental manipulations, including hearing loss. Using an auditory thalamocortical brain slice preparation, we find that hearing loss causes excitatory synapses to become stronger, inhibitory synapses to become weaker, and pyramidal neurons to become more excitable.

Although the brain slice experiments can tell us much about the cellular mechanisms that support plasticity, they are not able to address how the developing auditory nervous system encodes acoustic cues, or how this processing is perturbed by environmental manipulations. One of the primary stumbling blocks to studies of developmental function has been the use of anesthesia during in vivo recordings. Therefore, we have begun to explore new ways to measure auditory function in developing animals. In collaboration with Dan Turnbull's laboratory at the Skirball Institute, we are examining the activity pattern in mouse inferior colliculus using Mn-enhanced MRI. In collaboration with Mal Semple's lab, we have begun to record from single neurons in the inferior colliculus and cortex of awake gerbils.

Through study of each system, we hope to understand the cellular mechanisms that permit synaptic activity to influence the developing nervous system, and how they contribute to the construction of auditory computational circuits.

E-mail: sanes@cns.nyu.edu

Representative Publications

Sanes, D. H. (1990). An in vitro analysis of sound localization mechanisms in the gerbil lateral superior olive. J Neurosci 10, 3494-3506. [Reprint pdf file]

Sanes, D. H., Markowitz, S., Bernstein, J., and Wardlow, J. (1992). The influence of inhibitory afferents on the development of postsynaptic dendritic arbors. J Comp Neurol 321, 637-644. [Reprint pdf file] - Large File

Sanes, D. H. (1993). The development of synaptic function and integration in the central auditory system. J Neurosci 13, 2627-2637. [Reprint pdf file] - Large File

Sanes DH, Takacs C (1993) Activity-dependent refinement of inhibitory connections. European J Neurosci 5, 570-574. [Reprint pdf file]

Grothe, B., and Sanes, D. H. (1994). Synaptic inhibition influences the temporal response properties of gerbil medial superior olivary neurons: An in vitro study. J Neurosci 14, 1701-1709.

Hafidi, A., Sanes, D. H., and Hillman, D. E. (1995). Regeneration of central auditory connections in an organotypic culture system. European J Neurosci 15, 1298-1307.

Kotak VC, Sanes DH (1996) Developmental influence of glycinergic inhibition: Regulation of NMDA- mediated EPSPs. J Neurosci 16, 1836-1843. [Reprint pdf file]- Large File

Sanes DH, Hafidi A (1996) Glycinergic transmission regulates dendrite size in organotypic culture. J Neurobiol 31, 503-511. [Reprint pdf file]- Large File

Kotak VC, Sanes DH (1997) Deafferentation of glutamatergic afferents weakens synaptic strength in the developing auditory system. Eur J Neurosci 9, 2340-2347.

Sanes DH, Walsh EJ (1997) Development of Auditory Processing. In: Development of the Auditory System. (Eds, EW Rubel, AN Popper, RR Fay) Springer-Verlag: New York.

Lo Y-J, Rao SC, Sanes DH (1998) Modulation of calcium by inhibitory systems in the developing auditory system. Neurosci 83, 1075-1084. [Reprint pdf file]- Large File

Sanes DH, Malone BL, Semple MN (1998) Modulation of binaural level stimuli in gerbil inferior colliculus: role of synaptic inhibition. J Neurosci 18, 794-803. [Reprint pdf file]- Large File

Kotak VC, Korada S, Schwartz IR, Sanes DH (1998) A developmental shift from GABAergic to glycinergic transmission in the central auditory system. J Neurosci 18, 4646-4655. [Reprint pdf file]- Large File

Moore DR, Kotak VC, Sanes DH (1998) Commissural and lemniscal synaptic input to the gerbil inferior colliculus. J Neurophysiol 80, 2229-2236. [Reprint pdf file]

Sanes DH, McGee J, Walsh EJ (1998) Metabotropic glutamate receptor activation modulates auditory processing in the cochlear nucleus. J Neurophysiol 80, 209-217. [Reprint pdf file]

Thornton S, Semple MN, Sanes DH (1999) Development of auditory motion processing in the gerbil inferior colliculus. Eur J Neurosci 11, 1414-1420. [Reprint pdf file]- Large File

Fitzgerald KK, Sanes DH (1999) Serotonergic modulation of synapses in the developing gerbil lateral superior olive. J Neurophysiol 81, 2743-2752. [Reprint pdf file]

Hafidi A, Guo L, Sanes DH (1999) Transected commissural axons survive and grow, but do not cross a lesion site in organotypic culture. J Neurobiol 40, 267-280. [Reprint pdf file]- Large File

Vale C, Sanes DH (2000) Afferent regulation of inhibitory synaptic transmission in the developing auditory midbrain. J Neurosci 20, 1912-1921. [Reprint pdf file]- Large File

Kotak VK, Sanes DH (2000) Long-Lasting Inhibitory Synaptic Depression is Age- and Calcium Dependent. J Neurosci 20, 5820-5826. [Reprint pdf file]

Sanes DH, Friauf E (2000) Review: Development and influence of inhibition in the lateral superior olivary nucleus. Hear Res 147, 6-58. [Reprint pdf file]- Large File

Kotak VC, DiMattina C, Sanes DH (2001) GABAB and Trk receptor signaling mediates long lasting inhibitory synaptic depression. J Neurophysiol 86, 536-540. [Reprint pdf file]

Kotak VC, Sanes DH (2002) Postsynaptic kinase signaling underlies inhibitory synaptic plasticity. J Neurobiol 53, 36-43. [Reprint pdf file]

Vale C, Sanes DH (2002) The effect of bilateral deafness on excitatory synaptic strength in the auditory midbrain. Eur J Neurosci 16: 2394-2404. [Reprint pdf file]

Svirskis G, Kotak VC, Sanes DH, Rinzel J (2002) Enhancement of signal-to-noise ratio and phase locking by a low threshold outward current in auditory neurons. J Neurosci 22: 11019-11025. [Reprint pdf file]

Vale C, Schoorlemmer J, Sanes DH (2003) Deafness disrupts chloride transport and inhibitory synaptic transmission. J Neurosci 23: 7516-7524. [Reprint pdf file]

Chang EH, Kotak VC, Sanes DH (2003) Long-term depression of synaptic inhibition is expressed postsynaptically in the developing auditory system. J Neurophysiol 90: 1479Ð1488. [Reprint pdf file]

Green J, Kotak, VC, Sanes DH (2003) GABA and glycine evoked pH transients in developing auditory brain stem neurons. Brain Res 989: 122-127. [Reprint pdf file]

Kotak VC, Sanes DH (2003) Gain adjustment of inhibitory synapses in the auditory system. Biol Cybernetics 89: 363-370. [Reprint pdf file]

Hafidi A, Dastugue B, Grumet M, Sanes DH (2004) Factors preventing regeneration of inferior colliculus commissural axons in organotypic culture. J Comp Neurol 470: 80-92. [Reprint pdf file]

Svirskis G, Kotak VC, Sanes DH, Rinzel J (2004) Sodium along with low threshold potassium currents enhance coincidence detection of subthreshold noisy signals in MSO neurons. J Neurophysiol 91: 2465-2473. [Reprint pdf file]

Vale C, Juiz J, Moore, D, Sanes DH (2004) Unilateral hearing loss produces greater loss of inhibition in the contralateral inferior colliculus. Eur J Neurosci 20: 2133-2140. [Reprint pdf file]

Kotak VC, Fujisawa S, Lee FA, Karthikeyan O, Aoki C, Sanes DH (2005) Hearing loss raises excitability in the auditory cortex. J Neurosci 25: 3908-3918. [Reprint pdf file]

Yu X, Wadghiri YZ, Sanes DH, Turnbull DH (2005) In vivo auditory brain mapping in mice with Mn-enhanced MRI. Nat Neurosci 8: 961-968. [Reprint pdf file]

Green JS, Sanes DH (2005) Early appearance of inhibitory input to the MNTB supports binaural processing during development. J Neurophysiol 94: 3826-3825. [Reprint pdf file]

Sanes DH, Harris WA, Reh TA (2006) Development of the Nervous System, Academic Press: San Diego.

Kotak VC, Breithaupt AD, Sanes DH (2007) Developmental hearing loss eliminates LTP in the auditory cortex. Proc Natl Acad Sci USA 104: 3550-3555. [Reprint pdf file]

Xu H, Kotak VC, Sanes DH (2007) Conductive hearing loss disrupts synaptic and spike adaptation in developing auditory cortex. J Neurosci 27: 9417-9426. [Reprint pdf file]

Yu X, Sanes DH, Aristizabal O, Wadghiri YZ, Turnbull DH (2007) Large-scale reorganization of the tonotopic map in mouse auditory midbrain revealed by MRI. Proc Natl Acad Sci USA 104: 12193-12198. [Reprint pdf file]

Ter-Mikaelian M, Sanes DH, Semple MN (2007) Transformation of temporal properties between auditory midbrain and cortex in the awake Mongolian gerbil. J Neurosci 27: 6091-6102. [Reprint pdf file]

Yu X, Zou J, Babb JS, Johnson G, Sanes DH, Turnbull DH (2008) Statistical mapping of sound-evoked activity in the mouse auditory midbrain using Mn-enhanced MRI. Neuroimage 39: 223-230. [Reprint pdf file]

Kotak VC, Takesian AE, Sanes DH (2008) Hearing Loss Prevents the Maturation of GABAergic Transmission in the Auditory Cortex. Cereb Cortex Jan 24 [Epub ahead of print]. [Reprint pdf file]

Sarro EC, Kotak VC, Sanes DH, Aoki C (2008) Hearing Loss Alters the Subcellular Distribution of Presynaptic GAD and Postsynaptic GABAA Receptors in the Auditory Cortex. Cereb Cortex Apr 9 [Epub ahead of print]. [Reprint pdf file]