Metabotropic receptors shape oscillations in the thalamocortical circuit [electronic resource]

The thalamocortical circuit has a nested loop structure composed of reciprocal long-range projections between cortex and thalamus and reciprocal connections between excitatory relay thalamic nuclei and the inhibitory reticular thalamic nucleus. In addition, the propensity of thalamic neurons to fire post-inhibitory rebound bursts mediated by low-threshold calcium spikes renders the circuit susceptible to oscillations that can be induced both by increased excitation and increased inhibition, such as excessive excitatory cortical drive to thalamic reticular (RT) neurons or heightened inhibition of thalamocortical relay (TC) neurons by RT neurons. Thus the structural and intrinsic cellular characteristics of the thalamocortical circuit underlie its tendency to exhibit oscillatory activity, which ranges from normal sleep rhythms to the abnormal spike-wave discharges seen in absence epilepsy. Despite considerable knowledge of the network connectivity and cellular physiology that forms the basis for thalamocortical oscillations, the mechanisms that allow the network to be permissive to physiological oscillations while protecting against aberrant synchronous activity remain unclear. In this work, we investigated the modulatory function of two types of metabotropic receptors in thalamocortical oscillations. First, we examined the role of group III metabotropic receptors (mGluRs) which are uniquely located in the presynaptic active zone and typically act as autoreceptors or heteroceptors to depress synaptic release. Using optogenetic approaches for selective stimulation of axons in thalamic slices and pharmacologic manipulations of mGluR activity, we found that these receptors modulate short-term plasticity at two loci in the corticothalamic circuit in rats: glutamatergic cortical synapses onto RT neurons and GABAergic synapses onto TC neurons. The net effect of activation of these receptors was a strong and rapid suppression of thalamic oscillations in vitro, suggesting a functional role of these receptors to gate excessive activity in the corticothalamic circuit. Second, we studied how the modulation of metabotropic GABAB receptors at RT-TC synapses by GABA transporters (GATs) influences thalamic oscillations. We found that thalamic GAT activity bound the duration and periodicity of thalamic oscillations in a bidirectional manner. Through dynamic clamp experiments and modeling studies, we determined that changes in TC cell burst firing properties induced by GAT-modulation of GABAB IPSCs was sufficient to explain the effects on network oscillations, and proposed that GAT-modulated GABAB receptor activity contributes significantly to the shaping of physiological thalamic oscillations. In a final study, we present a novel computational method to isolate autaptic responses in neurons such as fast-spiking interneurons, for use in the study of autaptic function in normal physiology as well as in pathological states such as epilepsy. Overall, our findings demonstrate that the modulatory functions of metabotropic receptors such as mGluRs and GABAB receptors are associated with the maintenance of physiological oscillations in the thalamocortical circuit, and suggest that such receptors may be harnessed to develop therapeutics that can dampen or prevent abnormal oscillations while preserving normal network activity.

Advisor: Huguenard John primary advisor. Thesis advisor
Buckmaster Paul S. advisor. Thesis advisor
Reimer Richard J. advisor. Thesis advisor
Shatz Carla J. advisor. Thesis advisor