The tidy circuitry of the cerebellum, a hindbrain region involved in balance, coordination and sensorimotor integration, provides an important model system for understanding cellular mechanisms of learning. Learning can involve either an increase or decrease in transmission at a particular synapse, and this change can either be a temporary or permanent increase. Collectively, these processes are referred to as `synaptic plasticity'. In many regions of the central nervous system, NMDA receptors, neurotransmitter receptors located on postsynaptic sites, are involved in synaptic plasticity. In the cerebellum, however, the long-term depression of activity in the large output neurons, or Purkinje cells, is mediated by a different type of glutamate receptor, the AMPA receptor. NMDA receptors are present but in an unusual location: they are found presynaptically on interneurons that release the neurotransmitter GABA, which inhibits activity of the Purkinje cells. The unexpected location of NMDA receptors suggests that glutamate, previously believed to signal only in an anterograde fashion, i.e. from the presynaptic to the postsynaptic cell, could also be involved in retrograde signalling,from the postsynaptic to the presynaptic cell. A new paper by Ian Duguid and Trevor Smart demonstrates that the presynaptic NMDA receptors in the cerebellum are involved in a previously undescribed form of synaptic plasticity, which the authors call depolarization-induced potentiation of inhibition (DPI). Through a series of electrophysiological and immunocytochemical experiments, the authors revealed that the cellular mechanisms underlying DPI differ from those involved in a previously described form of plasticity, depolarization-induced suppression of inhibition (DSI),which occurs at the same synapse.

In DSI, repeated depolarization causes calcium to build up in the postsynaptic Purkinje cells, initiating release of endocannabinoids, a type of retrograde neurotransmitter, which activate cannabinoid receptors on the interneuron to temporarily suppress release of GABA. The resulting decrease in inhibitory input to the Purkinje cell lasts for tens of seconds.

Duguid and Smart found that both the underlying mechanism and the time course of DPI differ from those of DSI. In DPI, repetitive stimulation causes calcium to build up in Purkinje cells, leading to glutamate release, which in turn activates NMDA receptors on the presynaptic cell. This causes release of calcium from intracellular stores, resulting in enhanced release of GABA,increasing inhibitory input to Purkinje cells. The peak of DPI activity occurs after DSI has subsided and can last up to 10 min.

The ability of a neuron to strengthen activity at a synapse through DPI or weaken activity through DSI results in the capacity to weight incoming information; the impact of any given input will vary with the state of the neuron and the sum of all the synaptic inputs. Behavioural biologists have long known that behavioural responses can be context-specific, and neurobiologists understand that neuronal responses can be state-specific; for example, neurons in escape circuits will respond differently when an insect is walking than when it is flying. Given that the neural state of a circuit will vary with the behavioural state of an animal, it follows that synaptic events such as DPI and DSI contribute to context-specific behaviours. The new paper by Duguid and Smart demonstrates the existence of a novel form of state-dependent change in neural activity and adds to the growing list of mechanisms underlying synaptic plasticity.

Duguid, I. C. and Smart, T. G. (
). Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar interneuron-Purkinje cell synapses.
Nat. Neurosci.