Abstract
While it has been proposed that the conventional inhibitory neurotransmitter GABA can be excitatory in the mammalian brain, much remains to be learned concerning the circumstances and the cellular mechanisms governing potential excitatory GABA action. Using a combination of optogenetics and two-photon calcium imaging in vivo, we find that activation of chloride-permeable GABAA receptors in parallel fibers (PFs) of the cerebellar molecular layer of adult mice causes parallel fiber excitation. Stimulation of PFs at submaximal stimulus intensities leads to GABA release from molecular layer interneurons (MLIs), thus creating a positive feedback loop that enhances excitation near the center of an activated PF bundle. Our results imply that elevated chloride concentration can occur in specific intracellular compartments of mature mammalian neurons and suggest an excitatory role for GABAA receptors in the cerebellar cortex of adult mice.
Highlights
In recent years, potent effects of presynaptic axonal GABAA receptors (GABAARs) have been described in various regions of the mammalian brain (Trigo et al, 2008)
Inhibitory Effects of GABAAR Blockade A classical method to assess the polarity of GABAAR action is to compare neuronal activity before and after application of a GABAAR blocker; if such a blocker has an inhibitory effect, this indicates an excitatory effect of GABAARs in the signaling circuit (Ben-Ari et al, 1989)
In order to investigate possible excitatory GABAAR actions in the cerebellar cortex in vivo, we examined the effects of SR95531 on parallel fibers (PFs)-induced signals in molecular layer interneurons (MLIs), the GABAergic interneurons which are postsynaptic to PFs
Summary
Potent effects of presynaptic axonal GABAA receptors (GABAARs) have been described in various regions of the mammalian brain (Trigo et al, 2008). GABA is known to be the canonical inhibitory neurotransmitter at mammalian central synapses, activation of presynaptic GABAARs often results in excitation. In cerebellar slices, GABA spillover during molecular layer interneuron (MLI) activity leads to excitation of parallel fibers (PFs; Stell et al, 2007; Pugh and Jahr, 2011; Stell, 2011; Dellal et al, 2012). Because MLIs are excited by glutamate released by PFs, this raises the possibility of a positive feedback ‘‘GABA loop’’ where the excitability of a PF beam is enhanced by PFs exciting MLIs. Whereas the functioning of the various elements of this potential loop have been demonstrated separately in slices, it remains unclear whether the entire loop functions as a positive gain control for the PF-MLI circuit. Providing evidence for the existence and functional relevance of this loop in vivo is one of the major goals of this work
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