Regulation of Inhibition in a Sound Localization Circuit

This manuscript uses sound localization circuitry in the chick brainstem to examine the balance of inhibitory and excitatory neurotransmission maintained by neural circuits. This is a particular challenge in sensory systems, like the auditory system, in which this balance must be maintained despite variation in the acoustic environment. The studies described in this manuscript help clarify why and how inhibition is limited during two periods of changing auditory input: deafness and auditory development. In the cochlear nucleus, nucleus magnocellularis (NM), deprivation of excitatory input induced by deafness triggers neuronal death. While this neuronal death has previously been accredited to the loss of excitatory drive, the present experiments examine an alternative hypothesis: that inhibitory input to NM, which may also be affected by deafness, contributes to neuronal death in NM. Using an in vitro slice preparation in which excitatory input from the auditory nerve is absent, we pharmacologically altered GABA receptor activation in NM, and assayed an early marker of neuronal health, antigenicity for the ribosomal antibody Y10B (Y10B-ir). We found that GABA decreases Y10B-ir, and that GABAA activation is necessary for the GABA-induced effect. We further found that endogenous GABAA activation similarly decreases Y10B-ir and this decrease requires extracellular Ca2+ Our results suggest that, in the absence of excitatory input, endogenous activation of ionotropic GABAA receptors is detrimental to NM neurons. During auditory development, changes in membrane properties promote the ability of excitatory neurons in the brainstem to code aspects of sound, including the level and timing of a stimulus. Some of these changes coincide with the onset of hearing, suggesting that sound-driven activity in the nervous system produces developmental plasticity of ion channel expression. While it is known that the coding properties of excitatory neurons are modulated by inhibition in the mature system, it is unknown whether there are also developmental changes in the membrane properties of brainstem inhibitory neurons. We investigated the primary source of inhibition in the avian auditory brainstem, the superior olivary nucleus (SON), which displays sound-driven activity in mature animals. The present studies test the hypothesis that, as in excitatory neurons, the membrane properties of these inhibitory neurons also change following hearing onset. We examined SON neurons at different stages of auditory development: embryonic days 14-15 (E14-15), a time point at which cochlear ganglion neurons are just beginning to respond to sound, later stages of embryonic development (E18-19), and after hatching (P0-P1). We used in vitro whole-cell patch electrophysiology to explore physiological changes in SON. Age-related changes were observed at the level of a single spike and in multi-spiking behavior. In particular, tonic behavior, measured as a neuron's ability to sustain tonic firing over a range of current steps, became more common later in development. Voltage-clamp recordings and biophysical models were employed to examine how age-related increases in sodium and potassium currents enhance excitability in SON. Together the two sets of experiments suggest a new role for inhibition in the auditory brainstem. While it was previously known that inhibition complements excitation to improve auditory coding in a stable system, these experiments reveal that under less stable circumstances, inhibition actively contributes to plasticity in the brainstem circuit.