Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

Abstract

Although most theories of cerebellar function assume these synapses produce an excitatory sequential "beamlike" activation of PCs, numerous physiological studies have failed to find such beams. Using a computer model of the cerebellar cortex we predicted that the lack of PCs beams is explained by the concomitant pf activation of feedforward molecular layer inhibition. This prediction was tested, in vivo, by recording PCs sharing a common set of pfs before and after pharmacologically blocking inhibitory inputs. As predicted by the model, pf-induced beams of excitatory PC responses were seen only when inhibition was blocked. Blocking inhibition did not have a significant effect in the excitability of the cerebellar cortex. We conclude that pfs work in concert with feedforward cortical inhibition to regulate the excitability of the PC dendrite without directly influencing PC spiking output. This conclusion requires a significant reassessment of classical interpretations of the functional organization of the cerebellar cortex. I N T R O D U C T I O NThe distinctive orthogonal projection of the parallel fibers (pfs) through Purkinje cells (PCs) in the cerebellar cortex has dominated speculations concerning cerebellar function for more than 100 years

The advantages of linear information processing for cerebellar computation

“…As expected from asynchronous activation of granule cells, this method of stimulation produced an excitatory postsynaptic current (EPSC) in voltageclamped Purkinje cells that had a relatively slow time to peak (20 ms) and a slow, noisy decay to baseline (Fig. 1A), resembling the time course of activation of granule cells in vivo (15)(16)(17)(18)(19).…”

“…As has previously been shown in vivo, brief, discrete sensory stimuli in rats result in the asynchronous activity of patches of granule cells (15)(16)(17)(18)(19). The axons of these granule cells, parallel fibers, provide Purkinje cells with asynchronous inputs dispersed throughout their dendritic tree.…”

“…We find that, similar to that seen when patterns are encoded as pauses (3), synchronous inputs result in higher pattern recognition capacity. However, there is good evidence to suggest that parallel fiber inputs to Purkinje cells arrive asynchronously in vivo (15)(16)(17)(18)(19). Although the ability of Purkinje cells to recognize asynchronous patterns significantly degrades when encoding information as pauses, the linear algorithm remains remarkably proficient.…”

“…The pattern recognition capacity of Purkinje cells using pauses to encode patterns is considerably improved in the absence of inhibition and when inputs are assumed to be synchronous (3). Although what is commonly observed in vivo is asynchronous granule cell activity (15)(16)(17)(18)(19), there may be conditions in which granule cells provide synchronous input. Thus, we wondered whether the use of the linear algorithm enabled Purkinje cells to recognize a large number of patterns when their inputs were synchronously activated and how the capacity of Purkinje cells using the linear algorithm compared with those using pauses to encode information under similar conditions.…”

Topography and Response Timing of Intact Cerebellum Stained With Absorbance Voltage-Sensitive Dye

“…Cb inhibitory fields were initially described electrophysiologically as two bands lateral to the excitatory parallel fiber beam (Eccles et al 1966b), which are believed to limit the natural spread of those beams (Santamaria et al 2007) and play a role in sharpening the response timing of PC responses (Mittmann et al 2005). Optical recordings of transverse inhibitory bands indicate two distinct circuits in vitro (Cohen and Yarom 2000a), whereas in vivo recordings resulted in sagittal bands (Gao et al 2006).…”