Muscarinic ACh receptor-mediated control of thalamic activity via G_q/G₁₁-family G-proteins

Abstract

A genetic knock out was used to determine the specific contribution of G_q/G₁₁-family G-proteins to the function of thalamocortical relay (TC) neurons. Disruption of Gα_q function in a conditional forebrain-specific Gα_q/Gα₁₁-double-deficient mouse line $\left( {{{{\text{G $ \alpha $ }}_{\text{q}} } \mathord{\left/ {\vphantom {{{\text{G $ \alpha $ }}_{\text{q}} } {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}} \right. \kern-\nulldelimiterspace} {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}} \right)$ had no effects on the resting membrane potential (V _rest) and the amplitude of the standing outward current (I _SO). Stimulation of muscarinic acetylcholine (ACh) receptors (mAChR; muscarine, 50 μM) induced a decrease in I _SO amplitude in wild-type mice (36 ± 4%, n = 5), a constitutive Gα₁₁-deficient mouse line (${\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}$; 36 ± 3%, n = 8), and ${{{\text{G $ \alpha $ }}_{\text{q}} } \mathord{\left/ {\vphantom {{{\text{G $ \alpha $ }}_{\text{q}} } {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}} \right. \kern-\nulldelimiterspace} {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}$ (11 ± 2%, n = 16). Current-clamp recordings revealed a muscarine-induced positive shift in V _rest of 23 ± 2 mV (n = 6), 18 ± 5 mV (n = 5), and 2 ± 1 mV (n = 9) in wild type, ${\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}$, and ${{{\text{G $ \alpha $ }}_{\text{q}} } \mathord{\left/ {\vphantom {{{\text{G $ \alpha $ }}_{\text{q}} } {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}} \right. \kern-\nulldelimiterspace} {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}$, respectively. This depolarization was associated with a change in TC neuron activity from burst to tonic firing in wild type and ${\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }}$, but not in ${{{\text{G $ \alpha $ }}_{\text{q}} } \mathord{\left/ {\vphantom {{{\text{G $ \alpha $ }}_{\text{q}} } {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}} \right. \kern-\nulldelimiterspace} {{\text{G $ \alpha $ }}_{11}^{{ - \mathord{\left/ {\vphantom { - - }} \right. \kern-\nulldelimiterspace} - }} }}$. The use of specific antibodies and of pharmacological agents with preferred affinity points to the contribution of m₁AChR and m₃AChR. In conclusion, we present two novel aspects of the physiology of the thalamocortical system by demonstrating that the depolarization of TC neurons, which is induced by the action of transmitters of ascending brainstem fibers, is governed roughly equally by both m₁AChR and m₃AChR and is transduced by Gα_q but not by Gα₁₁.