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Various ion channels and transmitter receptors are responsible for maintaining the proper function of neurons (Debanne et al. 2003; Perez-Otano and Ehlers 2005). The properties of SOC neurons are likewise controlled and regulated by distinct channels and receptors. Two major subdivisions of receptors can be classified in the mammalian brain: ionotropic and metabotropic receptors. Ionotropic receptors (or ligand-gated ion channels) possess a pore region and are characterized by their direct action on ion flow. Upon transmitter binding, their pore region is permeable for ions; hence an outward or inward current is built up, depending on the receptor, its ion permeability, the actual potential and the present ion concentration. Some examples for ionotropic receptors have been mentioned above as e.g. glycine receptors and GABAA receptors. These receptors usually generate hyperpolarizing currents

in the SOC and function as chloride channels upon activation. Nevertheless, at neonatal stages the action of GABA and glycine is depolarizing with major implications for cell development (Kakazu et al. 1999; Kandler and Friauf 1995; Lohrke et al. 2005). Other examples for ionotropic receptors would be the excitatory AMPA and Kainate receptors as well as NMDA receptors which conduct mostly sodium, potassium and in some cases

calcium. Metabotropic receptors, in contrast, mediate indirect inhibitory or excitatory action. These receptors utilize neurotransmitters as ligands, which, when bound to the receptors, initiate cascades that can lead to channel-opening or other cellular effects. Metabotropic receptors mostly activate intracellular G-proteins and kinases which usually have manifold effects on cell properties. However, because the signaling is not direct as for ionotropic receptors, effects normally take longer to develop but also last longer. Recent studies described such a coupling to G-proteins for several classes of receptors, therefore classified as G-protein-coupled receptors (GPCRs). Attwood and Findlay (1994) have made great effort in defining the probably biggest class of GPCRs, the rhodopsin-like GPCRs, which comprises serotoninergic, dopaminergic and endocannabinoid neurotransmitter signaling (Attwood and Findlay 1994; Binzen et al. 2006; Guo and Ikeda 2004). Other well-investigated and important classes regarding signal regulation are metabotropic GPCRs including metabotropic glutamate receptors and GABAB receptors (GABABRs) (Kaupmann et al. 1997;

Nakanishi 1994).

First evidence that the MSO expresses GABABRs was recently provided by histochemical

studies in the Mongolian gerbil and the Rhesus Macaque (Heise et al. 2005; Hilbig et al. 2007). GABABRs are relevant for auditory processing as physiological studies with focus on

the AVCN, LSO and MNTB showed (Kotak et al. 2001; Lim et al. 2000; Magnusson et al. 2008; Sakaba and Neher 2003). Several functional implications have been suggested so far. The activation of GABABRs was proposed, for instance, to help developing the temporal

precision of LSO neurons by eliminating inappropriate inhibitory projections (Kotak and Sanes 2000). Furthermore, dendritically released GABA controls synaptic input by a GABABR based feedback mechanism. This in turn, allows LSO neurons to adapt and extend

their range of coding in order to match the sensory environment and accurately represent auditory space (Magnusson et al. 2008). Additionally, the fidelity of spike trains could be increased in MNTB neurons after activation of GABABRs since the downmodulation of

calcium current is most important for all forms of synchronous release (Sakaba and Neher 2003). The putatively underlying principles of such control mechanisms based on the modulation of effective transmitter amount will be introduced in the following.

From a systematic view, GABABRs are part of the seven-transmembrane domain receptor

superfamily and are closely associated with G-proteins (Fig.1.6). Opposing to GABAARs,

GABABRs do not open upon GABA binding but mediate indirect effects via a G-protein

cascade. GABABRs can be situated both, pre- and postsynaptically, however, the effects

mediated by these receptors are differently established at the pre- and the postsynapse (Yamada et al. 1999).

Functional GABABRs at the postsynaptic site activate G-protein coupled inwardly rectifying

potassium channels (GIRK channels) which are permeable to K+_{-ions, thus hyperpolarize the}

neuron upon activation (Jones et al. 1998; Luscher et al. 1997). The activation is enabled by a conformation change of the G-protein itself. The βγ-subunit of the heterotrimeric G-protein

dissociates from the α-subunit and binds to GIRK channels thereby increasing the open-state

of the channel. Due to the concentration gradient of K+_{, an efflux of potassium is achieved,}

which is long lasting (seconds) compared to ionotropic signaling (milliseconds) (Isaacson 1998). Several forms of the α-subunit exist making it difficult to explain some effects

straightforward. The αs-subunit e.g. activates the andenylate cyclase which synthesizes

cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Depending on synaptic activity, cAMP levels increase and modulate the open-probability of HCN channels (DiFrancesco 1999). On the other hand, the αi-subunit inhibits the synthesis of cAMP from

ATP, and thus can cause completely opposite effects upon activation. Hence, the knowledge of the present composition of G-protein subunits is of great importance for the comprehension of GABABR mediated effects.

Figure 1.6: The GABAB receptor and two

possible modes of action. Both subunits (R1 and R2) of the GABABR need to be coupled for

functionality. Upon activation by the neurotransmitter GABA, the GABABR induces a

conformation change in the bound heterotrimeric G-protein, which causes an exchange of GDP for GTP. In this high-energy state, the G-protein dissociates in its βγ-subunit and α-subunit, both

further mediating distinct intrinsic processes. The

βγ-subunit, for example, activates K+ permeable

GIRK channels and inhibits calcium channels whereas the α-subunit activates adenylate

cyclase resulting in production of cAMP from ATP. Source: http://www.sigmaaldrich.com

Yet, GABABRs are also expressed and functionally membrane bound at the presynapse. The

most relevant mechanism here is the lowering of intracellular Ca2+ _{by inactivation of calcium}

channels (Isaacson 1998; Misgeld et al. 1995; Takahashi et al. 1998; Wojcik and Neff 1984). However, this feature is not solely restricted to the presynapse since studies also reported inhibition of calcium channels at the postsynaptic site (Harayama et al. 1998; Mann-Metzer and Yarom 2002). Calcium is at both locations essential for the proper function of the SNARE complex, a protein complex which brings intracellular vesicles in close distance to the cell’s membrane, thus easing exocytosis. Due to the lowered Ca2+ _{concentration, the}

probability for a conformation change in the SNARE complex is decreased. Therefore neurotransmitter vesicles are less likely to fuse with the cell membrane. Conclusively, the

release probability of neurotransmitter is decreased resulting in a presynaptically mediated depression of synaptic strength. Since it was demonstrated that GABABRs are expressed at

inhibitory as well as at excitatory presynapses, the change in release probability can affect the inhibition as well as the excitation (Kabashima et al. 1997; Lei and McBain 2003; Lim et al. 2000).