Differences in Transmission Properties and Susceptibility to Long-Term Depression Reveal Functional Specialization of Ascending Axon and Parallel Fiber Synapses to Purkinje Cells

Abstract

An understanding of the patterns of mossy fiber transmission to Purkinje cells, via granule cell axons, is fundamental to models of cerebellar cortical signaling and processing. Early theories assumed that mossy fiber input is widely disseminated across the cerebellar cortex along beams of parallel fibers, which spread for several millimeters across the cerebellar cortex. Direct evidence for this has, however, proved controversial, leading to the development of an alternative hypothesis that mossy fiber inputs to the cerebral cortex are in fact vertically organized such that the ascending segment of the granule axon carries a greater synaptic weight than the parallel fiber segment. Here, we report that ascending axon synapses are selectively resistant to cerebellar long-term depression and that they release transmitter with higher mean release probabilities and mean quantal amplitudes than parallel fiber synapses. This novel specialization of synapses formed by different segments of the same axon not only explains the reported patterns of granule cell3 Purkinje cell transmission across the cerebellar cortex but also reveals an additional level of functionality and complexity of cerebellar processing. Consequently, ascending axon synapses represent a new element of cortical signal processing that should be distinguished from parallel fiber synapses in future experimental and theoretical studies of cerebellar function.

Differential Susceptibility to Synaptic Plasticity Reveals a Functional Specialization of Ascending Axon and Parallel Fiber Synapses to Cerebellar Purkinje Cells

“…If this is the principal role of the ascending axon, then plasticity would serve little or no function and so the absence of any form of long-term plasticity at these synapses lends support to this notion. Parallel fiber synapses have lower quantal amplitudes and release probabilities than those formed by ascending axons, and they can sustain short-term facilitation for longer, allowing them to transmit bursts of higher frequency information (Sims and Hartell, 2005). We now show that they can also readily undergo presynaptic and postsynaptic forms of long-term plasticity.…”

“…Although the absolute degree of pathway selectivity produced by GC layer and molecular layer stimulation remains to be verified experimentally, it is sufficient to reveal clear differences in the transmission properties of synapses in each pathway (Sims and Hartell, 2005). Presynaptic and postsynaptic specialization at ascending axon and parallel fiber synapses confers each segment of the GC axon with distinct transmission properties.…”

“…In a coronal slice orientation, the T-shaped structure of GC axons is preserved, allowing a relatively selective activation of parallel fiber and ascending axon synapses to the same PC (Sims and Hartell, 2005). Parallel fiber synapses were activated by stimulating through aCSF-filled patch electrodes, with resistances of 1-2 M⍀, placed midway between the PC layer and pia mater to a depth of 50 -100 m, 150 -300 m lateral to the recorded PC.…”

“…Because this would effectively reduce the mean quantal amplitude and because parallel fiber synapses have lower mean quantal amplitudes than those formed by ascending axons (Sims and Hartell, 2005), we compared the extent to which each synaptic pathway to single PCs underwent two well characterized forms of LTD. Combining CF activation with parallel fiber stimulation, using a protocol designed to replicate physiological patterns of GC and climbing fiber activity (LT-D CJ ), produced LTD of parallel fiber pathway EPSCs but not ascending axon responses.…”

“…These observations have revitalized a hypothesis in which synapses formed by the ascending segment of the GC axon, which represent 20% of the total GC input to PCs (Gundappa-Sulur et al, 1999), provide the principal excitatory drive to the cerebellar cortex (Llinás, 1982;Santamaria et al, 2002). Ascending axon synapses release transmitter with a higher mean probability than those formed by parallel fibers and display larger postsynaptic responses to quantal release events (Sims and Hartell, 2005). Furthermore, whereas up to 85% of synapses formed by parallel fibers appear to be electrically silent, this proportion is much reduced at ascending axon synapses (Isope and Barbour, 2002).…”