This issue contains a speculative hypothesis by Professor Max Bennett on the neurobiology of depression. This hypothesis links alterations in a regenerative loop at central glutamatergic synapses involving both neurons and glial cells, especially in the hippocampus, to alterations in the functional state of neural networks related to mood disorders. To assist readers of the journal evaluate this hypothesis, this editorial summarises historical neurobiological theories of depression, and developments over the past decade which provide a background to this hypothesis. The original amine hypothesis of depression is now over forty years old [1] and arose from three clinical-pharmacological observations. Drugs, such as reserpine, which deplete pre-synaptic stores of the amine neurotransmitters serotonin and/or noradrenaline, and reduce availability of these amine neurotransmitters in synapses induce depression in some people. Tricyclic antidepressant drugs relieve depression by increasing the availability of amine neurotransmitters in the synapse by inhibiting their reuptake into pre-synaptic nerve terminals. Monoamine oxidase inhibitors relieve depression by increasing the availability of amine neurotransmitters in the synapse by inhibiting the breakdown of these chemicals in the synapse. This amine depletion theory of depression guided neurobiological research on depression for a number of decades, and in a simplistic form has been accepted by some members of the public who hold a view that ‘‘depression is a serotonin deficiency’’. Even from the early days of neurobiological depression research there were many doubts about a simplistic amine deficiency theory including concerns that the pharmacological effects of antidepressant drugs were almost immediate, but clinical response typically took many days or even weeks for therapeutic benefit. During the 1980s research then focussed on alterations in preand/or postsynaptic monoamine receptor function, rather than just synaptic cleft depletion of neurotransmitters. Over the past decade there has been a revolution in how we are thinking about the neurobiological basis of depression, with a major shift away from a focus on the synapse alone. Changing paradigms include thinking about the neural circuits involved in depression, the waxing and waning of neurogenesis and synaptogenesis, and realising that there may be important abnormalities of glial cells rather than just abnormalities of neuron to neuron synapses. These shifts in paradigm have occurred within broader developments in neuroscience, which now appreciate that the adult brain does not have a fixed number of neurons which slowly die, but adult brains are growing new neurons, and connections between neurons are in a state of dynamic flux (plasticity). With these changing paradigms, we can no longer just think of depression as an abnormality of the connections (synapses) between statically wired neurons, but the wires (neurons) themselves, their connections (synapses), and their supporting structures (glial cells), are in a state of dynamic change. Peter R. Joyce, Professor and Editor-in-Chief