Microanatomy of dendritic spines: emerging principles of synaptic pathology in psychiatric and neurological disease

Psychiatric and neurologic disorders ranging from mental retardation to addiction are accompanied by structural and functional alterations of synaptic connections in the brain. Such alterations include abnormal density and morphology of dendritic spines, synapse loss, and aberrant synaptic signaling and plasticity. Recent work is revealing an unexpectedly complex biochemical and subcellular organization of dendritic spines. In this review, we highlight the molecular interplay between functional domains of the spine, including the postsynaptic density, the actin cytoskeleton, and membrane trafficking domains. This research points to an emerging level of analysis—a microanatomical understanding of synaptic physiology—that will be critical for discerning how synapses operate in normal physiologic states and for identifying and reversing microscopic changes in psychiatric and neurologic disease.