Biphasic Cholinergic Synaptic Transmission Controls Action Potential Activity in Thalamic Reticular Nucleus Neurons

Abstract

Cholinergic neurons in the basal forebrain and the brain stem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular ACh levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Here, we demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that ACh release evoked by low-frequency stimulation leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic α4β2 nicotinic (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. In addition, ACh can bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, short trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our study demonstrates fast and precise synaptic E-I signaling mediated by ACh, suggesting novel computational mechanisms for the cholinergic control of neuronal activity in thalamic circuits.

GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility

“…Although this theta abnormality is most prominent in occipital regions, it seems to disappear by adolescence (Laan et al, 1997), perhaps explaining why we did not record significant enhancements in theta power in adult Ube3a STOP/p+ or Ube3a FLOX/p+ ::Gad2-Cre mice despite recording from V1 (Figure 6). Future work in AS models should focus on factors known to affect TRN neuron excitability and synchrony – including relative levels of excitatory and inhibitory synaptic drive, the integrity of gap junctions (Proulx et al, 2006; Lee et al, 2014), the expression of T-type calcium channels (Tsakiridou et al, 1995; Zhang et al, 2009), and cholinergic input (McCormick and Prince, 1986; Sun et al, 2013). However, intracortical GABAergic mechanisms that underlie pathological spike-wave discharges also remain of interest, especially those that engage disinhibitory circuitry (Pi et al, 2013; Hall et al, 2015).…”

Thalamic Inhibition: Diverse Sources, Diverse Scales

“…For example, cholinergic neurons of the basal forebrain and the brainstem project to TRN neurons [27], exerting a powerful postsynaptic response with a fast excitatory nicotinic component and a slower muscarinic inhibitory component [28]. This same logic applies to GABAergic inputs to the TRN which arise from an ill-defined zone along the basal forebrain – external globus pallidus border possibly involving some lateral hypothalamic regions as well [29–31]…”

Adaptation to prolonged neuromodulation in cortical cultures: an invariable return to network synchrony

“…Consequently, and if synchrony represents a strong attractor as prior studies suggest [39,49], escaping it might depend on finely tuned combinations of multiple factors, such as neuronal membrane potential, excitability, probability of neurotransmitter release and synaptic depression. All these (and others) have been previously shown to be affected by (cholinergic) neuromodulation in complex and intricate manners [26,40,55,57,62,65,83,[91][92][93][94][95] which differ from one cell type to another [96]. Consequently, the (homeostatic) recovery [25,38] of one or more of these finely tuned factors, in one or more neuronal types, might move the system back into a parameter space within which synchrony naturally emerges [49].…”

“…The phasic mode consists of fast transients of high ACh concentrations, spanning a time scale of seconds and even subseconds [101]. Recent studies suggest that responses to cholinergic innervation can be sensitive to precise (subsecond) timing of cholinergic neuron activity ( [91,103] and references therein). In contrast, the regime of cholinergic input in the experiments described here resembled a combination of phasic and tonic modes, with cholinergic concentrations varying more than a hundredfold, but over time scales of many seconds and minutes.…”