Spontaneous neural activity is a common feature of developing sensory systems and has been implicated in controlling the survival, maturation and wiring of their respective brain circuits. In the developing auditory system, spontaneous activity is initiated within the cochlea and leads to bursts of action potentials in spiral ganglion neurons (SGNs). Little is known about how this temporally patterned activity affects the development of cochlea. In this thesis, I investigated whether activation of N-methyl-D-aspartate receptors (NMDARs), which have been shown to play an important role in synaptic maturation in the central nervous system (CNS), is involved in generating this sound-independent activity and regulating the survival of neurons in the developing cochlea. I determined that functional NMDARs are expressed by SGNs during the prehearing period, are activated at inner hair cell (IHC)-SGN synapses, enable glutamate-mediated Ca2+ influx, contribute substantially to the excitation of individual SGNs by enhancing their repetitive firing in response to each IHC Ca2+ spike, and promote synchronous activation among groups of SGNs. To test whether activation of NMDARs affects SGN development, I pharmacologically blocked these receptors in cochlear explant cultures, and genetically removed GluN1 (previously termed NR1), a subunit required for the formation of functional NMDARs, from SGNs in vivo. Loss of NMDAR signaling in SGNs reduced neuronal survival and partially impaired dendritic refinement. These studies indicate that patterned spontaneous bursts of activity by SGNs require the activation of NMDARs during the prehearing period, and contribute to the maturation of SGNs leading to their integration into auditory circuitry.
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Expression and Function of NMDA Receptors in the Developing Cochlea
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