Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand [(11)C]UCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that [(11)C]UCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, [(11)C]UCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders.

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Recovery from neuronal activation requires rapid clearance of potassium ions (K ؉ ) and restoration of osmotic equilibrium. The predominant water channel protein in brain, aquaporin-4 (AQP4), is concentrated in the astrocyte end-feet membranes adjacent to blood vessels in neocortex and cerebellum by association with ␣-syntrophin protein. Although AQP4 has been implicated in the pathogenesis of brain edema, its functions in normal brain physiology are uncertain. In this study, we used immunogold electron microscopy to compare hippocampus of WT and ␣-syntrophin-null mice (␣-Syn ؊/؊ ). We found that <10% of AQP4 immunogold labeling is retained in the perivascular astrocyte end-feet membranes of the ␣-Syn ؊/؊ mice, whereas labeling of the inwardly rectifying K ؉ channel, Kir4.1, is largely unchanged. Activity-dependent changes in K ؉ clearance were studied in hippocampal slices to test whether AQP4 and K ؉ channels work in concert to achieve isosmotic clearance of K ؉ after neuronal activation. Microelectrode recordings of extracellular K ؉ ([K ؉ ]o) from the target zones of Schaffer collaterals and perforant path were obtained after 5-, 10-, and 20-Hz orthodromic stimulations. K ؉ clearance was prolonged up to 2-fold in ␣-Syn ؊/؊ mice compared with WT mice. Furthermore, the intensity of hyperthermia-induced epileptic seizures was increased in approximately half of the ␣-Syn ؊/؊ mice. These studies lead us to propose that water flux through perivascular AQP4 is needed to sustain efficient removal of K ؉ after neuronal activation.