A general theory of neural development holds that sensory experience can influence the functional properties of synapses during a finite period of maturation (i.e., critical period). Consistent with this idea, cortical inhibitory synapse strength is reduced dramatically following even moderate developmental hearing loss. However, whether inhibitory synapse maturation displays a critical period is poorly understood. Further, there are no strategies to restore normal inhibitory function in animals raised with hearing loss. Our core hypothesis is that cortical inhibitory synapse function is particularly vulnerable to hearing loss before adulthood, and normal function can be rescued during a critical period. There are three related aims:
Aim 1 will first determine whether the effect of developmental conductive hearing loss (CHL) on auditory cortex inhibitory synapse function persists into adulthood. We will then ask whether inhibitory function in auditory cortex is more vulnerable to CHL that occurs during early development, than to CHL that occurs in late juvenile or adult animals. In all cases, spontaneous and evoked inhibitory synaptic currents will be recorded in a thalamocortical brain slice, including paired recordings between inhibitory interneurons and pyramidal cells.
Aim 2 will determine whether inhibitory synapse deficits induced by developmental CHL can impair auditory processing. Using a large-scale auditory cortex network model that incorporates parameters based on in situ measurements, we will evaluate how specific inhibitory properties influence the simulations of auditory cortex coding. Comparisons will be made between 'control'networks and 'CHL networks'in which one or more inhibitory property is modified to reflect experimental observations.
Aim 3 will determine whether normal inhibitory function can be permanently rescued in animals with developmental CHL by rearing them with a GABAergic agonist for 6 days. Animals will then be permitted to reach adulthood, when inhibitory synaptic properties will be assessed. The agonists to be used will activate either 11 subunit-containing GABAA receptors, or GABAA and GABAB receptors or GABAB receptors only. To determine whether there is a critical period during which inhibitory function can be rescued, animals with early CHL will be drug-treated later during juvenile development or as adults. Finally, if we find that adult CHL produces inhibitory synaptic dysfunction, then we will determine whether drug-rearing can rescue inhibition in these animals. Together, these data will provide the first analysis of an inhibitory synapse critical period in the auditory system, and a first attempt to pharmacologically rescue central nervous system function following developmental hearing loss.
Profound hearing loss in children can produce long-lasting deficits in auditory perception and language acquisition. It has been suggested that central nervous system deficits that are caused by hearing loss could adversely impact auditory processing and perception. Therefore, restoration of central function could be essential for the development of normal auditory performance. To address this issue, we will explore whether auditory cortex synapse function is particularly vulnerable to hearing loss, and evaluate a new strategy for restoring normal synapse function in animals with developmental hearing loss.
|Gai, Yan; Kotak, Vibhakar C; Sanes, Dan H et al. (2014) On the localization of complex sounds: temporal encoding based on input-slope coincidence detection of envelopes. J Neurophysiol 112:802-13|
|Kotak, Vibhakar C; Takesian, Anne E; MacKenzie, Patricia C et al. (2013) Rescue of inhibitory synapse strength following developmental hearing loss. PLoS One 8:e53438|
|Takesian, Anne E; Kotak, Vibhakar C; Sharma, Neeti et al. (2013) Hearing loss differentially affects thalamic drive to two cortical interneuron subtypes. J Neurophysiol 110:999-1008|
|Takesian, Anne E; Kotak, Vibhakar C; Sanes, Dan H (2012) Age-dependent effect of hearing loss on cortical inhibitory synapse function. J Neurophysiol 107:937-47|
|Sanes, Dan H; Kotak, Vibhakar C (2011) Developmental plasticity of auditory cortical inhibitory synapses. Hear Res 279:140-8|
|Sanes, Dan H; Woolley, Sarah M N (2011) A behavioral framework to guide research on central auditory development and plasticity. Neuron 72:912-29|