GABA_B and NMDA Receptors Contribute to Spindle-Like Oscillations in Rat Thalamus In Vitro

Abstract

Thalamic slice preparations, in which intrathalamic connectivity between the reticular nucleus and relay nuclei is maintained, are capable of sustaining rhythmic burst firing activity in rodents and ferret. These in vitro oscillations occur spontaneously in the ferret and have frequencies (6-10 Hz) within the range of sleep spindles observed in vivo. In the rat, mainly lower frequency (2-4 Hz) oscillations, evoked under conditions of low bath [Mg(2+)] and/or GABA(A) receptor blockade, have been described. Here we show that faster rhythms in the range of 4-9 Hz can be evoked in rat thalamic slices by electrical stimulation of the internal capsule and also occur spontaneously. When bath [Mg(2+)] was 2 mM, these spindle-like oscillations were most common in a brief developmental time window, peaking at postnatal day 12 (P12). The oscillations were almost completely blocked by the GABA(A) receptor antagonist picrotoxin, and, in some cases, the frequency of oscillations was increased by the GABA(B) receptor antagonist CGP-35348. The selective blockade of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by the antagonists 2-amino-5-phosphonovaleric acid or 1,2,3,4-Tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), respectively, significantly shortened oscillations but did not completely block them. A combination of the two drugs was necessary to abolish oscillatory activity. The barbituate pentobarbital, which enhances GABA(A)R responses, initially slowed and synchronized oscillations before completely blocking them. When bath [Mg(2+)] was reduced from 2 to 0.65 mM, evoked oscillations became more robust and were often accompanied by spontaneously arising oscillations. Under these conditions, GABA(A) receptor blockade no longer inhibited oscillations, but instead converted them into the slow, synchronous rhythms that have been observed in other studies. The effects of GABA(B) or NMDA receptor blockade were more pronounced in 0.65 mM than in 2 mM external [Mg(2+)]. Thus spindle-like oscillations occur in rat thalamic slices in vitro, and we find that, in addition to the previously demonstrated contributions of GABA(A) and AMPA receptors to these oscillations, NMDA and GABA(B) receptors are also involved. The strong influence of external [Mg(2+)] on GABAergic pharmacology and a contribution of NMDA receptors during oscillations suggest a link between the excitability of NMDA receptors and the activation of GABA(B)R-mediated inhibitory postsynaptic currents.

Coordination of Slow Waves With Sleep Spindles Predicts Sleep-Dependent Memory Consolidation in Schizophrenia

“…SWs emerge spontaneously in the neocortex, even after cortical de-afferentation 51 , but can also be elicited by optogenetic manipulation of TRN and thalamocortical neurons 52,53 suggesting that thalamic input shapes SW expression 22 . In contrast, spindle frequency rhythms are seen in the isolated TRN 54,55 , but not in the isolated cortex or other thalamic nuclei 55,56 . Cortical feedback to the TRN and thalamocortical neurons, however, synchronizes spindles across cortical regions 57,58 and can initiate and terminate spindles 59 .…”

Thalamo-cortical communication, glutamatergic neurotransmission and neural oscillations: A unique window into the origins of ScZ?

“…In particular, as noted above, TRN GABAergic neurons express NMDA-Rs that can be activated at resting membrane potentials due to the presence of GluN2C/2D subunits (Gentet and Ulrich, 2003;Jacobsen et al, 2001a;Jacobsen et al, 2001b;Zhang et al, 2012a;Zhang et al, 2009a). Indeed, many ScZ-related neurobiological changes in the PFC can be induced secondary to TRN dysfunction .…”

“…Moreover, data from preclinical studies in rodents have provided strong support for the hypothesis that NMDA-Rs critically impact on TC-interactions (Morris et al, 2005). NMDA-R blockage in vitro inhibits spindle-like oscillations in slices of rodent thalamus (Jacobsen et al, 2001a). Systemic NMDA-R antagonists disrupt the firing of rodent MD neurons (Santana et al, 2011b), and increase hippocampal delta oscillatory activity via a site of action within the thalamus (Zhang et al, 2012b).…”

Dynamic GABAAReceptor Subtype-Specific Modulation of the Synchrony and Duration of Thalamic Oscillations

“…Larger contributions from GABA B receptors, which slow evoked thalamic oscillations (Jacobsen et al, 2001), may also explain why the period of oscillations was longer in rats than in mice.…”