Human brain imaging has identified structural changes in gray and white matter that occur with learning. However, ascribing imaging measures to underlying cellular and molecular events is challenging. Here, we review human neuroimaging findings of structural plasticity and then discuss cellular and molecular level changes that could underlie observed imaging effects. We propose that greater dialogue between researchers in these different fields will help to facilitate cross talk between cellular and systems level explanations of how learning sculpts brain structure.

White matter is the brain region underlying the gray matter cortex, composed of neuronal fibers coated with electrical insulation called myelin. Previously of interest in demyelinating diseases such as multiple sclerosis, myelin is attracting new interest as an unexpected contributor to a wide range of psychiatric disorders, including depression and schizophrenia. This is stimulating research into myelin involvement in normal cognitive function, learning and IQ. Myelination continues for decades in the human brain; it is modifiable by experience, and it affects information processing by regulating the velocity and synchrony of impulse conduction between distant cortical regions. Cell-culture studies have identified molecular mechanisms regulating myelination by electrical activity, and myelin also limits the critical period for learning through inhibitory proteins that suppress axon sprouting and synaptogenesis.

Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors that modulate intracellular calcium and cyclic AMP. This enables glia to detect neural activity and communicate among other glial cells by releasing ATP through membrane channels and vesicles. Through purinergic signalling, impulse activity regulates glial proliferation, motility, survival, differentiation and myelination, and facilitates interactions between neurons, and vascular and immune system cells. Interactions among purinergic, growth factor and cytokine signalling regulate synaptic strength, development and responses to injury. We review the involvement of ATP and adenosine receptors in neuron-glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance.Functional interactions between neurons and glia have been suspected for decades, but how glia might detect neural activity, communicate with other glial cells, and influence neuronal function have proved to be difficult questions to answer. Before purinergic signalling was considered, several other mechanisms were explored for neuron-glia communication, but each of these was comparatively limited. Astrocytes can communicate through gap junctions 1 , but this was viewed in the context of maintaining homeostasis of extracellular potassium. Bursts of action potentials fired by axons release potassium, which is taken up by astrocytes and dispersed through an astrocytic syncytium coupled by gap junctions. The build up of potassium during prolonged high-frequency stimulation can produce calcium transients in myelinating glia (Schwann cells) in the sciatic nerve 2 , but stimulation in the normal physiological range does not have this effect. Glial membrane receptors can be activated by many different neurotransmitters 3 , although this is most relevant to glia having access to neurotransmitter spreading beyond the synaptic cleft 4 . Purinergic signalling has emerged as the most pervasive mechanism for intercellular communication in the nervous system, affecting communication between many types of neurons, all types of glia, and vascular cells 5,6 . NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHere we examine the history and recent developments of neuron-glia signalling and the prominent role of extracellular ATP in these interactions. We review the mechanisms of ATP release from cells and the large family of membrane receptors for extracellular ATP and adenosine. The pharmacology and expression of these receptors in glia are summarized, and the consequences of purinergic signalling in neuron-glia communication are discussed, with an emphasis on glial regulation of synaptic transmission, activity-dependent myelination, and nervous system response to injury. ATP in cell-cell signallingATP has long been recognized as an intracellular energy source, although its acceptance as an extracellular signalling molecule has take...