Reciprocal Inhibitory Connections and Network Synchrony in the Mammalian Thalamus

M. M. Huntsman
1999 Science  
Neuronal rhythmic activities within thalamocortical circuits range from partially synchronous oscillations during normal sleep to hypersynchrony associated with absence epilepsy. It has been proposed that recurrent inhibition within the thalamic reticular nucleus serves to reduce synchrony and thus prevents seizures. Inhibition and synchrony in slices from mice devoid of the ␥-aminobutyric acid type-A (GABA A ) receptor ␤ 3 subunit were examined, because in rodent thalamus, ␤ 3 is largely
more » ... 3 is largely restricted to reticular nucleus. In ␤ 3 knockout mice, GABA A -mediated inhibition was nearly abolished in reticular nucleus, but was unaffected in relay cells. In addition, oscillatory synchrony was dramatically intensified. Thus, recurrent inhibitory connections within reticular nucleus act as "desynchronizers." Inhibitory circuits arising in the reticular thalamic nucleus (RTN) play important roles in various oscillatory activities related to sleep and some epilepsies (1-5). The major projections of inhibitory neurons in RTN are onto relay neurons in dorsal thalamus, but recurrent collaterals also provide intranuclear inhibition (6). It has been hypothesized that the latter connections regulate RTN inhibitory output during thalamic oscillations and prevent the hypersynchrony of generalized absence epilepsy (7-9). Inhibitory postsynaptic currents (IPSCs) in RTN neurons are mediated by the major inhibitory neurotransmitter, ␥-aminobutyric acid, through GABA type A receptors. IPSCs in RTN differ from those in relay neurons (10), presumably due to differences in GABA A receptor subunit composition (11), which ultimately affect ligand affinity, channel gating, and modulation (12). In rodent thalamus, ␤ 3 is one of a limited number of GABA A subunit mRNAs expressed in RTN and is absent from relay nuclei (11). Despite a lack of widespread gene expression in the adult rodent brain, ␤ 3 knockout mice (␤ 3 Ϫ/Ϫ ) exhibit many neurological impairments and are considered a model of Angelman's syndrome in humans (13). We examined inhibitory function in thalamic slices of ␤ 3 knockout mice to test whether elimination of this subunit would suppress intra-RTN inhibition and thus promote intrathalamic synchrony (14) . Voltage clamp recordings (15) were performed in the presence of GABA B and ionotropic glutamatergic blockers to specifically isolate GABA A receptor-mediated IPSCs (10, 16). Spontaneous IPSCs (sIPSCs) in RTN neurons from controls were long lasting, with an average weighted decay time constant ( D,W ) of 74.7 Ϯ 5.9 ms (n ϭ 19; Fig. 1, C and D) . Infrequent sIPSCs were observed in RTN neurons of ␤ 3 knockout mice and were much smaller and more brief than in wild-type (␤ 3 ϩ/ϩ ) littermates. sIPSC decay was almost three times faster ( D,W ϭ 27.4 Ϯ 2.4 ms, n ϭ 26, P Ͻ 0.0001) in knockouts, whereas sIPSC amplitude and frequency in RTN were reduced by more than 50% (P Ͻ 0.0001; Fig. 1, A through D) . Overall inhibitory efficacy was estimated by integrating total sIPSC charge per 1-s interval. In controls, the total charge was 3840 Ϯ 1130 pC/s (n ϭ 19), compared to a much reduced value of 130 Ϯ 20 pC/s (n ϭ 26, P Ͻ 0.0005) in ␤ 3 knockouts. By contrast, excitatory connections were intact in RTN neurons of knockout mice. Spontaneous excitatory postsynaptic currents (sEPSCs) were comparable in amplitude (11 versus 14 pA in ␤ 3 ϩ/ϩ and ␤ 3 Ϫ/Ϫ , respectively), half-width (1.1 versus 1.2 ms), and frequency (2.1 versus 3.0 Hz, n ϭ 7 each). Inhibition in thalamic relay neurons of the ventrobasal (VB) complex was unchanged in ␤ 3 knockout mice-sIPSC amplitudes, decay kinetics, and frequency were comparable in wild-type control and knockout mice (Fig. 1 , E through H). As in rat (10), sIPSC decay was faster in VB neurons (Fig. 1G ) than in
doi:10.1126/science.283.5401.541 pmid:9915702 fatcat:43spiungr5fjbbriz47pggsjm4