Johns Hopkins School of Medicine

Neuron-glial cell communication in brain development, circuit function and disease.

The nervous system is comprised of two main cell types – neurons and non-neuronal glial cells – that together enable it to process and interpret sensory input, make decisions, and rapidly execute complex behaviors. Although the basic tenets of neural signaling, from action potential generation to synaptic transmission, have been defined, the roles of distinct glial cell types in both supporting and modulating this activity remain less well understood. Our lab is interested in defining the mechanisms used for communication between neurons and glial cells, understanding how these modes of communication are used to shape brain development and information processing in brain circuits, and the consequences of disrupted neuron-glial signaling in disease. We use a diverse range of methods in our studies, including generation of transgenic mice to allow selective visualization and manipulation of distinct glial cell types, 2- and 3-photon imaging to analyze their dynamics in vivo, and electrophysiological methods to record rapid modes of intercellular interaction. Our current studies are focused in three areas.

 1.        Oligodendrocyte precursor cells, oligodendrogenesis and myelination.

The CNS contains a widely distributed population of lineage-restricted progenitors that retain the capacity to differentiate into oligodendrocytes throughout life. Thus, these oligodendrocyte precursor cells (OPCs) are crucial to form myelin during brain development, enhance myelination during learning (adaptive myelination), and repair myelin after injury or disease such as multiple sclerosis. Our studies seek to define the molecular pathways that regulate the proliferation and differentiation of these cells, control the integration of newly formed oligodendrocytes within existing brain circuits, and influence the regeneration of oligodendrocytes after demyelination.

 2.        Glial modulation of auditory system development.

Our studies indicate that glial-like supporting cells in the developing inner ear (cochlea) are responsible for inducing spontaneous neural activity in the auditory system prior to hearing onset. Supporting cells located next to inner hair cells release ATP before ear canal opening, which initiates a cascade of events that ultimately leads to bursts of action potentials in spiral ganglion neurons in the absence of sound. These bursts propagate through central auditory centers to adjust their excitability, refine their frequency sensitivity, and control the size of sound processing regions. Our current studies seek to define the molecular mechanisms responsible for generating this activity and use this knowledge to determine how it controls refinement of the circuits involved in hearing.

 3.        Astrocyte neuromodulation in the brain.

Astrocytes are highly ramified glial cells in the CNS that perform numerous key functions, including neurotransmitter reuptake, physical isolation of synapses, metabolic support, and ion homeostasis. Both molecular and physiological studies indicate that astrocytes express receptors for neurotransmitters and are a target of norepinephrine that is released during periods of heightened arousal. Our studies seek to determine the behavioral contexts in which astrocytes are activated by neuromodulators, the consequences of this activation for neural circuit activity on both short- and long time-scales, and the contribution of these signaling pathways to dysfunctional states in disease.