Effects of Neurotrophin-3 on Intrinsic Neuronal Properties at a Central Auditory Structure

Neurotrophins, a class of growth factor proteins that control neuronal proliferation, morphology, and apoptosis, are found ubiquitously throughout the nervous system. One particular neurotrophin (NT-3) and its cognate tyrosine receptor kinase (TrkC) have recently received attention as a possible therapeutic target for synaptopathic sensorineural hearing loss. Additionally, research shows that NT-3-TrkC signaling plays a role in establishing the sensory organization of frequency topology (ie, tonotopic order) in the cochlea of the peripheral inner ear. However, the neurotrophic effects of NT-3 on central auditory properties are unclear. In this study we examined whether NT-3-TrkC signaling affects the intrinsic electrophysiological properties at a first-order central auditory structure in chicken, known as nucleus magnocellularis (NM). Here, the expression pattern of specific neurotrophins is well known and tightly regulated. By using whole-cell patch-clamp electrophysiology, we show that NT-3 application to brainstem slices does not affect intrinsic properties of high-frequency neuronal regions but had robust effects for low-frequency neurons, altering voltage-dependent potassium functions, action potential repolarization kinetics, and passive membrane properties. We suggest that NT-3 may contribute to the precise establishment and organization of tonotopy in the central auditory pathway by playing a specialized role in regulating the development of intrinsic neuronal properties of low-frequency NM neurons.

Intrinsic Neuronal Properties, Neural Networks, and Behavior

Complex interactions among large numbers of neurons are required to generate most behaviors. Studies in biological model systems—such as the stomatogastric ganglion of lobsters and crabs, and neurons controlling reproduction in Aplysia—have provided insights into how the intrinsic electrical properties of neurons shape network activity and animal behavior. Some neurons can participate simultaneously in more than a single network, and the properties of a network may be modulated by the actions of neurotransmitters and hormones. Changes in the intrinsic excitability of a single command neuron or command systems of neurons can trigger a complicated and long-lasting behavior. Cellular mechanisms that regulate the accuracy of timing of action potentials, both within a network and in different parts of a dendritic tree, are also important for the interpretation of sensory information and for the ability of a neuron to modify the strength of the connections it makes with other neurons.

Targeted disruption of layer 4 during development increases GABAA receptor neurotransmission in the neocortex

Cortical dysplasia (CD) associates with clinical pathologies, including epilepsy and mental retardation. CD results from impaired migration of immature neurons to their cortical targets, leading to clustering of neural cells and changes in cortical properties. We developed a CD model by administering methylazoxymethanol (MAM), an anti-mitotic, to pregnant ferrets on embryonic day 33; this leads to reduction in cortical thickness in addition to redistribution and increased expression of GABAA receptors (GABAAR). We evaluated the impact of MAM treatment on GABAAR-mediated synaptic transmission in postnatal day 0–1 neurons, leaving the ganglionic eminence (GE) and in layer 2/3 pyramidal cells of postnatal day 28–38 ferrets. Embryonic day 33 MAM treatment significantly increases the amplitude and frequency of spontaneous GABAAR-mediated inhibitory postsynaptic currents (IPSCs) in the cells leaving the GE. In older MAM-treated animals, the amplitude and frequency of GABAAR-mediated spontaneous IPSCs in layer 2/3 pyramidal cells is increased, as are the amplitude and frequency of miniature IPSCs. The kinetics of GABAAR opening also altered following treatment with MAM. Western blot analysis shows that the expression of the GABAAα3R and GABAAγ2R subunits amplified in our model animals. We did not observe any significant change in the passive properties of either the layer 2/3 pyramidal cells or cells leaving the GE after MAM treatment. These observations reinforce the idea that synaptic neurotransmission through GABAAR enhances following treatment with MAM and coincides with our finding of increased GABAAαR expression within the upper cortical layers. Overall, we demonstrate that small amounts of toxins delivered during corticogenesis can result in long-lasting changes in ambient expression of GABAAR that influence intrinsic neuronal properties.