In vivo imaging of synaptic components and functions in neuropsychiatric disorders

Makoto Higuchi, Jun Maeda, Masaki Tokunaga, Tetsuya Suhara

Molecular Imaging Center, National Institute of Radiological Sciences

Abnormal neurotransmission is a molecular basis of clinical manifestations in neuropsychiatric disorders, while contributions of specific neurotransmitter systems and neuronal circuitry to characteristic symptoms are largely unknown. Key processes connecting core pathological alterations to dysregulated neurotransmissions are also yet to be clarified. Positron emission tomography (PET) allows in vivo measurements of synaptic components including neuroreceptors and neurotransmitter transporters, and an assessment of synaptic neurotransmitter concentrations based on competition between endogenous transmitters and exogenous radioligands for target molecules. Moreover, functional coupling between two distinct classes of neuroreceptors can be examined by PET imaging of one class while pharmacologically regulating another. Our in vivo PET studies have demonstrated disturbed release of serotonin in the hippocampus of mice heterozygously deficient of calcium/calmodulin-dependent protein kinase IIα, which are known to exhibit cognitive impairments and emotional abnormalities. We have also observed increase of metabotropic glutamate receptor subtype 5 (mGluR5) parallel to amyloid β peptide (Aβ) deposition in amyloid precursor protein transgenic mice by PET detection of amyloid and mGluR5, in consistency with a previous report on Aβ-induced intensification of mGluR5 on excitatory synapses. Impacts of these pathological changes in mGluR5 on functional coupling between mGluR5 and ionotropic glutamate receptors are currently being investigated with the aid of molecular imaging techniques. Local and large-scale neuronal networks mediating between altered neurotransmitter systems and symptoms would be elucidated by a combined use of PET and functional magnetic resonance imaging.

Address correspondence to Dr. Makoto Higuchi, Molecular Imaging Center, National Institute of Radiological Sciences (4-9-1 Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan)