Dances with black widow spiders: Dysregulation of glutamate signalling enters centre stage in ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with impairments across the lifespan. The persistence of ADHD is associated with considerable liability to neuropsychiatric co-morbidity such as depression, anxiety and substance use disorder. The substantial heritability of ADHD is well documented and recent genome-wide analyses for risk genes revealed synaptic adhesion molecules (e.g. latrophilin-3, LPHN3; fibronectin leucine-rich repeat transmembrane protein-3, FLRT3), glutamate receptors (e.g. metabotropic glutamate receptor-5, GRM5) and mediators of intracellular signalling pathways (e.g. nitric oxide synthase-1, NOS1). These genes encode principal components of the molecular machinery that connects pre- and postsynaptic neurons, facilitates glutamatergic transmission, controls synaptic plasticity and empowers intersecting neural circuits to process and refine information. Thus, identification of genetic variation affecting molecules essential for the formation, specification and function of excitatory synapses is refocusing research efforts on ADHD pathogenesis to include the long-neglected glutamate system.