Dan H. Sanes

Development and plasticity of the auditory CNS

Despite enormous advances in our understanding of growth and formation of the nervous system, we know little about the function of developing networks or the computations they perform. Sensory and motor processing continue to mature long after the mammalian brain looks adult-like, and the environment can exert a powerful influence during this time. Perhaps the most devastating example of this effect occurs when early hearing loss can disrupt central auditory processing skills and language acquisition.

Our lab studies the development of central auditory processing, and its relationship to the emergence of mature behavioral performance in normal and deafened animals.

Inhibitory Synaptic Plasticity During Development
Much of our cellular research has concentrated on the development and plasticity of inhibitory synapses. For historical reasons, the vast majority of work in neuroscience has considered the development of excitatory connections, such as those that activate muscles or those carry information from the retina to the forebrain. However, inhibitory synapses are essential to every computation performed by the central nervous system, and their dysfunction is increasingly tied to developmental disorders such as autism or learning disabilities.

Thus, our lab has found that inhibitory projections in the auditory brain stem become more precise in during development - like excitatory systems - and this process is influenced by normal hearing. If the activity of inhibitory connections does influence their stability during development, then there must be a mechanism to control their gain. We have identified one such development mechanism that controls the strength of immature inhibitory synapses, and which may support the refinement of these contacts in response to the auditory experience. As it turns out, GABA signaling is crucial for synaptic plasticity: a specific GABA_B receptor antagonist blocks inhibitory long-term depression. 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.

Early Hearing Loss Disrupts Inhibitory Synapse Function
When it became clear that inhibitory synapse function is influenced by the auditory environment, we were motivated to explore the implications for hearing loss. In fact, childhood hearing loss creates a major impediment to the acquisition of speech, language, reading and most learning that depends on aural communication. For decades these deficits were attributed solely to the limitations imposed by a damaged cochlea. However, we have shown that hearing loss leads to rapid, systematic changes in the strength of nearly all synaptic connections in the central auditory nervous system.

In general, we find that early hearing loss leads to a dramatic decrease of inhibitory synaptic strength and an increase in excitatory strength. This is true for both the auditory midbrain and the auditory cortex. 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.

Many of these synaptic changes can be observed following a relatively mild hearing loss (in which the cochlea is intact and the animal can hear, albeit with higher thresholds). These synaptic changes can be described as homeostatic in that they increase neuron excitability, thereby resisting the initial challenge. These findings suggest that the deaf central auditory nervous system may operate quite differently when it is activated (for example, by a electrical prosthesis), and draw attention to the importance of considering both peripheral and central factors when trying to explain the perceptual deficits associated with early hearing loss.

Until a few years ago, we would have concluded that the changes in synaptic gain which attend early hearing loss can largely explain many of the known behavioral deficits, including the difficulties with learning. However, weÕve recently discovered that that the synaptic mechanisms commonly thought to support learning (i.e., long-term potentiation) do not mature properly in the auditory cortex following early hearing loss. This is true for both excitatory and inhibitory synapses (Kotal et al., 2007; Xu et al., Soc Neurosci Abs, 2008). The general implication is that sensory deficits may lead to learning problems because brain mechanisms that support learning fail to emerge.

Maturation of Auditory Processing and Behavioral Performance
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 have examined the maturation of frequency-specific activity patterns 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. These recordings suggest that the coding of dynamic stimuli, such as sinusoidally amplitude modulated tones, matures over a relatively long postnatal time. In collaboration with Jack Kelly, we assess the behavioral performance of developing animals and those reared with early hearing loss. These studies indicate that behavioral performance in juvenile animals is quite immature, and may parallel the maturation of auditory cortex coding properties.

Through each of these approaches, we seek 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.

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. [Publishers URL]

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 18: 2098-2108. [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]