GABA_A receptors increase excitability and conduction velocity of cerebellar parallel fiber axons

Abstract

Dellal SS, Luo R, Otis TS. GABA A receptors increase excitability and conduction velocity of cerebellar parallel fiber axons. J Neurophysiol 107: 2958 -2970. First published February 29, 2012 doi:10.1152/jn.01028.2011In the adult mammalian brain, GABA A receptors (GABA A Rs) are responsible for the predominant forms of synaptic inhibition, but these receptors can excite neurons when the chloride equilibrium potential (E Cl ) is depolarized. In many mature neurons, GABA A Rs are found on presynaptic terminals where they exert depolarizing effects. To understand whether excitatory GABA action affects axonal function, we used transverse cerebellar slices to measure the effects of photolysis of caged GABA on the initiation and propagation of compound parallel fiber (PF) action potentials (APs). Photolysis of caged GABA increased the amplitude and conduction velocity of PF APs; GABA reuptake blockers and a positive modulator of GABA A Rs enhanced these effects. In contrast, a modulator selective for ␦-subunit-containing GABA A Rs did not enhance these effects and responsiveness remained in ␦ Ϫ/Ϫ mice, arguing that ␦-subunit-containing GABA A Rs are not required. Synaptically released GABA also increased PF excitability, indicating that the mechanism is engaged by physiological signals. A Hodgkin-Huxleystyle compartmental model of the PF axon and granule cell body was constructed, and this model recapitulated the GABA-dependent decrease in AP threshold and the increase in conduction velocity, features that were sensitive to E Cl and to the voltage dependence of sodium channel inactivation. The model also predicts that axonal GABA A Rs could affect orthodromic spike initiation. We conclude that GABA acting on cerebellar PFs facilitates both spike generation and propagation, allowing axons of granule cells to passively integrate signals from inhibitory interneurons and influence information flow in the input layer to the cerebellar cortex.␥-aminobutyric acid; presynaptic modulation; axonal excitability; ␦-subunit; fiber volley; caged ␥-aminobutyric acid THE CLASSICAL STUDIES OF MUSCLE afferent inputs to spinal motor neurons that gave rise to the concept of presynaptic inhibition also eventually led to the first identification of presynaptic GABA A receptors (GABA A Rs) (Eccles et al. 1963). Subsequent work by many laboratories demonstrated that this GABA A R-mediated presynaptic inhibition results from a depolarizing action of GABA on presynaptic afferent terminals (Rudomin and Schmidt 1999). Since those initial findings, GABA A Rs have been observed on presynaptic terminals in a variety of brain regions, including auditory brain stem, ventral tegmental area, hypothalamus, amygdala, hippocampus, cerebellum, and cortex, and in most of these locations GABA has been found to be depolarizing ( Although there have been many studies on the consequences of presynaptic GABA A Rs on synaptic transmission, relatively little is known about whether these receptors affect axonal excitability. To directly test whether transient acti...

Activation of Axonal Receptors by GABA Spillover Increases Somatic Firing

“…Our previous work has demonstrated that activation of axonal GABA A Rs by exogenous GABA can affect AP firing in cerebellar granule cells (Pugh and Jahr, 2011). This result was confirmed by a computer modeling study of axonal GABA A R activation and AP initiation in the same cells (Dellal et al, 2012). To our knowledge, the present work is the first showing that activation of axonal receptors by release of neurotransmitter from nearby synapses can affect integration and AP initiation at the soma.…”

“…The excitability index of cells lacking an axon was significantly different from cells with an intact axon ( p ϭ 0.03, unpaired t test), confirming that the change in excitability results from axonal and not somatodendritic GABA A Rs. Previous work suggests that E Cl in parallel fibers is depolarized from rest, near AP threshold (Stell et al, 2007; Pugh and Jahr, 2011; Dellal et al, 2012). To mimic physiological conditions more closely, we repeated these experiments with a lower-chloride internal (E Cl of Ϫ50 mV).…”

“…It is well established that parallel fibers express functional GABA A Rs, that their activation depolarizes the axon, and that they increase release probability at parallel fiber synapses (Stell et al, 2007;Pugh and Jahr, 2011;Stell, 2011;Dellal et al, 2012). Previous experimental studies applying exogenous GABA to granule cell axons by iontophoresis (Pugh and Jahr, 2011) and computer modeling studies (Dellal et al, 2012) have suggested that GABA A R-mediated axonal depolarizations can also increase the probability of AP firing near the soma. However, the time course and concentration of GABA resulting from spillover from neighboring inhibitory synapses is likely very different from that produced by iontophoresis.…”

Rapid regulation of tonic GABA currents in cultured rat hippocampal neurons

“…Voltage-dependent increases of tonic conductance are expected to affect the behavior of hippocampal neurons and networks (Glykys and Mody 2006;Pavlov et al 2009). This would typically be an inhibitory effect, but if it occurred during periods of intracellular Cl Ϫ accumulation, voltage-dependent potentiation could enhance an excitatory influence of GABA currents (Dellal et al 2012;Dzhala et al 2010). Nonvesicular GABA release by GAT1.…”

Multitasking in Gonadotropin-Releasing Hormone Neuron Dendrites

“…In the cerebellum, a similar situation exists for locally released GABA onto parallel fibre axons [57]. Synaptic events that occur in dendrites can also passively propagate for very long distances down axons [34,37].…”