Specialized connectivity of molecular layer interneuron subtypes leads to disinhibition and synchronous inhibition of cerebellar Purkinje cells.

Molecular layer interneurons (MLIs) account for approximately 80% of the inhibitory interneurons in the cerebellar cortex and are vital to cerebellar processing. MLIs are thought to primarily inhibit Purkinje cells (PCs) and suppress the plasticity of synapses onto PCs. MLIs also inhibit, and are electrically coupled to, other MLIs, but the functional significance of these connections is not known. Here, we find that two recently recognized MLI subtypes, MLI1 and MLI2, have a highly specialized connectivity that allows them to serve distinct functional roles. MLI1s primarily inhibit PCs, are electrically coupled to each other, fire synchronously with other MLI1s on the millisecond timescale in vivo, and synchronously pause PC firing. MLI2s are not electrically coupled, primarily inhibit MLI1s and disinhibit PCs, and are well suited to gating cerebellar-dependent behavior and learning. The synchronous firing of electrically coupled MLI1s and disinhibition provided by MLI2s require a major re-evaluation of cerebellar processing.

Cerebellar circuits for disinhibition and synchronous inhibition.

The cerebellar cortex contributes to diverse behaviors by transforming mossy fiber inputs into predictions in the form of Purkinje cell (PC) outputs, and then refining those predictions1. Molecular layer interneurons (MLIs) account for approximately 80% of the inhibitory interneurons in the cerebellar cortex2, and are vital to cerebellar processing1,3. MLIs are thought to primarily inhibit PCs and suppress the plasticity of excitatory synapses onto PCs. MLIs also inhibit, and are electrically coupled to, other MLIs4-7, but the functional significance of these connections is not known1,3. Behavioral studies suggest that cerebellar-dependent learning is gated by disinhibition of PCs, but the source of such disinhibition has not been identified8. Here we find that two recently recognized MLI subtypes2, MLI1 and MLI2, have highly specialized connectivity that allows them to serve very different functional roles. MLI1s primarily inhibit PCs, are electrically coupled to each other, fire synchronously with other MLI1s on the millisecond time scale in vivo, and synchronously pause PC firing. MLI2s are not electrically coupled, they primarily inhibit MLI1s and disinhibit PCs, and are well suited to gating cerebellar-dependent learning8. These findings require a major reevaluation of processing within the cerebellum in which disinhibition, a powerful circuit motif present in the cerebral cortex and elsewhere9-17, greatly increases the computational power and flexibility of the cerebellum. They also suggest that millisecond time scale synchronous firing of electrically-coupled MLI1s helps regulate the output of the cerebellar cortex by synchronously pausing PC firing, which has been shown to evoke precisely-timed firing in PC targets18.

Hyperpolarization induces a long-term increase in the spontaneous firing rate of cerebellar Golgi cells.

Golgi cells (GoCs) are inhibitory interneurons that influence the cerebellar cortical response to sensory input by regulating the excitability of the granule cell layer. While GoC inhibition is essential for normal motor coordination, little is known about the circuit dynamics that govern the activity of these cells. In particular, although GoC spontaneous spiking influences the extent of inhibition and gain throughout the granule cell layer, it is not known whether this spontaneous activity can be modulated in a long-term manner. Here we describe a form of long-term plasticity that regulates the spontaneous firing rate of GoCs in the rat cerebellar cortex. We find that membrane hyperpolarization, either by mGluR2 activation of potassium channels, or by somatic current injection, induces a long-lasting increase in GoC spontaneous firing. This spike rate plasticity appears to result from a strong reduction in the spike after hyperpolarization. Pharmacological manipulations suggest the involvement of calcium-calmodulin-dependent kinase II and calcium-activated potassium channels in mediating these firing rate increases. As a consequence of this plasticity, GoC spontaneous spiking is selectively enhanced, but the gain of evoked spiking is unaffected. Hence, this plasticity is well suited for selectively regulating the tonic output of GoCs rather than their sensory-evoked responses.