Mixed Inhibitory Synaptic Balance Correlates with Glutamatergic Synaptic Phenotype in Cerebellar Unipolar Brush Cells

Abstract

Inhibitory synapses display a great diversity through varying combinations of presynaptic GABA and glycine release and postsynaptic expression of GABA and glycine receptor subtypes. We hypothesized that increased flexibility offered by this dual transmitter system might serve to tune the inhibitory phenotype to the properties of afferent excitatory synaptic inputs in individual cells. Vestibulocerebellar unipolar brush cells (UBC) receive a single glutamatergic synapse from a mossy fiber (MF), which makes them an ideal model to study excitatory-inhibitory interactions. We examined the functional phenotypes of mixed inhibitory synapses formed by Golgi interneurons onto UBCs in rat slices. We show that glycinergic IPSCs are present in all cells. An additional GABAergic component of large amplitude is only detected in a subpopulation of UBCs. This GABAergic phenotype is strictly anti-correlated with the expression of type II, but not type I, metabotropic glutamate receptors (mGluRs) at the MF synapse. Immunohistochemical stainings and agonist applications show that global UBC expression of glycine and GABA A receptors matches the pharmacological profile of IPSCs. Paired recordings of Golgi cells and UBCs confirm the postsynaptic origin of the inhibitory phenotype, including the slow kinetics of glycinergic components. These results strongly suggest the presence of a functional coregulation of excitatory and inhibitory phenotypes at the single-cell level. We propose that slow glycinergic IPSCs may provide an inhibitory tone, setting the gain of the MF to UBC relay, whereas large and fast GABAergic IPSCs may in addition control spike timing in mGluRII-negative UBCs.

A temporal basis for predicting the sensory consequences of motor commands in an electric fish

“…Though we had no way to specifically target UBCs and hence cannot provide a complete account of their properties, our in vivo intracellular recordings suggest that they generate temporally diverse and delayed responses that are faithfully recoded in granule cells. Though in vivo responses to discrete inputs have yet to be described for UBCs in the mammalian cerebellum or dorsal cochlear nucleus, in vitro studies have documented a variety of synaptic and intrinsic mechanisms capable of generating prolonged and/or delayed responses 26–30 . These include rebound firing 29 , regular tonic firing 29 , and inhibitory synaptic input from Golgi cells 30 —the key ingredients for delayed responses suggested by our in vivo intracellular recordings.…”

“…Though in vivo responses to discrete inputs have yet to be described for UBCs in the mammalian cerebellum or dorsal cochlear nucleus, in vitro studies have documented a variety of synaptic and intrinsic mechanisms capable of generating prolonged and/or delayed responses 26–30 . These include rebound firing 29 , regular tonic firing 29 , and inhibitory synaptic input from Golgi cells 30 —the key ingredients for delayed responses suggested by our in vivo intracellular recordings. Hence the functions for UBCs established here may extend to other circuits in which they are found.…”

Early Onset of Ataxia in Moonwalker Mice Is Accompanied by Complete Ablation of Type II Unipolar Brush Cells and Purkinje Cell Dysfunction

“…These lobules contain high densities of unipolar brush cells (UBCs), whose distribution suggests they could be the TRPC3-expressing cells. Similar to the granule cells, the UBCs transduce excitatory inputs of a variety of mossy fibers (for review, see Mugnaini et al, 2011) under inhibitory control by the Golgi cells (Dugué et al, 2005;Rousseau et al, 2012); in turn, UBC axons innervate pools of granule cells, ultimately affecting the output of the overlying PCs. Thus, UBCs provide a powerful amplification system for afferent inputs to the cerebellar cortex (Rossi et al, 1995;Diño et al, 2000;Mugnaini et al, 2011).…”

Glycine receptors in nervous tissue and their functional role

“…Глицин (Gly) выполняет в организме целый ряд жизненно важных функций [1][2][3][4][5][6][7][8][9]. Он входит в состав многих белков и биологически активных соединений, из него синтезируются порфириновые кольца гема и пуриновые основания [10].…”

“…Рецепторы к Gly, локализованные во многих участках головного и спинного мозга, оказывают тормозное воздействие на нейроны, уменьшая выделение возбуждающих аминокислот [1][2][3]. В то же время глицин выступает в роли коагониста рецептора g-аминобутирата (GABA-R) и глутаматного рецептора NMDA-R [4][5][6][7][8].…”