GABA signaling in the thalamus

Inhibition of neuronal activity in networks of the mammalian central nervous
system is essential for all fundamental brain functions, ranging from perception, to
consciousness, to action. Both exacerbation and diminution of inhibition dramatically
affect our behavioral capacities, indicating that, in the healthy brain, strength and
dynamics of inhibition must be precisely balanced.
Inhibitory functions are primarily accomplished by neurons releasing the
neurotransmitter GABA. According to their wide variety of functions, GABAergic
neurons show a tremendous diversity in morphological, biochemical and functional
characteristics. The combination of these diverse properties allows the brain to
generate interneurons acting as, for examples, filters, co-incidence detectors or
contrast enhancers. GABAergic signaling in thalamus plays an essential role in
controlling sensory information flow from the periphery to the cortical processing
centers, and in generating sleep-related neuronal rhythms. Surprisingly, however, the
diversity of GABAergic neurons is remarkably limited in thalamic networks. Both
functions mentioned have been tightly associated with two homogeneous groups of
GABAergic neurons arising within thalamic nuclei or within the nucleus reticularis, a
shell of inhibitory nuclei surrounding the dorsal thalamus.
The results arising from the present thesis challenge the view that the diversity
of GABAergic signaling in thalamus is comparatively limited and proposes that, to
fully understand GABAergic signaling in thalamus, at least two additional aspects
have to be considered. First, it shows that GABAergic signaling arising from the
nucleus reticularis can have a profound effect on the synthesis of second messenger
compounds that are important in the control of neuronal rhythmicities and in the statedependent
control of gene expression. Second, it demonstrates the functional
relevance of a previously undescribed extrathalamic and extrareticular inhibitory
pathway that arises within the anterior pretectal nuclei, indicating that the architecture
of GABAergic signaling in thalamus has to be complemented by a conceptually
novel, powerful afferent pathway.
The first part investigates the modulation of cAMP synthesis by GABA in
thalamocortical neurons through the activation of the Gi-coupled GABAB receptors.
GABAB receptors can provide two different cAMP signals in the neurons. First,
GABAB receptor activation depresses the level of cAMP inside thalamocortical
neurons. However, a large and long cAMP signal is observed when GABAB
receptors are activated concomitantly with b-adrenergic receptors, which are Gscoupled
receptors. In the presence of GABAB receptor agonists, the moderate cAMP
increase produced by b-adrenergic receptor activation is transformed into a large
synthesis of cAMP. Remarkably, the activation of the GABAB receptors at the
synapses between reticular neurons and thalamocortical neurons also potentiates the
effects of b-adrenergic receptors. Thus, GABAB receptors modulate cAMP signals at
synapses that are important for the regulation of the state of arousal.
The second part provides the first electrophysiological description of synaptic
connections between the anterior pretectum group and the thalamic higher-order
nuclei. Electric stimulation in the anterior pretectum group evoked inhibitory
postsynaptic responses (IPS) in the thalamocortical neurons of the higher-order
nuclei. We showed that the IPS responses were mediated via the GABAA receptors
activated through monosynaptic connections between the APT and the higher-order
nuclei. Functionally, the anterior pretectum modulated the discharge properties of the
thalamocortical neurons, suggesting an important role of this nucleus in the dialogue
between the thalamus and the cortex.