Functional Specificity of Gα_qand Gα₁₁in the Cholinergic and Glutamatergic Modulation of Potassium Currents and Excitability in Hippocampal Neurons

Abstract

In hippocampal and other cortical neurons, action potentials are followed by a slow afterhyperpolarization (sAHP) generated by the activation of small-conductance Ca 2ϩ -activated K ϩ channels and controlling spike frequency adaptation. The corresponding current, the apamin-insensitive sI AHP , is a well known target of modulation by different neurotransmitters, including acetylcholine (via M 3 receptors) and glutamate (via metabotropic glutamate receptor 5, mGluR 5 ), in CA1 pyramidal neurons. The actions of muscarinic and mGluR agonists on sI AHP involve the activation of pertussis toxin-insensitive G-proteins. However, the pharmacological tools available so far did not permit the identification of the specific G-protein subtypes transducing the effects of M 3 and mGluR 5 on sI AHP . In the present study, we used mice deficient in the G␣ q and G␣ 11 genes to investigate the specific role of these G-protein ␣ subunits in the cholinergic and glutamatergic modulation of sI AHP in CA1 neurons. In mice lacking G␣ q , the effects of muscarinic and glutamatergic agonists on sI AHP were nearly abolished, whereas ␤-adrenergic agonists acting via G␣ s were still fully effective. Modulation of sI AHP by any of these agonists was instead unchanged in mice lacking G␣ 11 . The additional depolarizing effects of muscarinic and glutamatergic agonists on CA1 neurons were preserved in mice lacking G␣ q or G␣ 11 . Thus, G␣ q , but not G␣ 11 , mediates specifically the action of cholinergic and glutamatergic agonists on sI AHP , without affecting the modulation of other currents. These results provide to our knowledge one of the first examples of the functional specificity of G␣ q and G␣ 11 in central neurons. Key words: G-protein; muscarinic; metabotropic glutamate; calcium-activated potassium current; afterhyperpolarization; CA1 pyramidal neuronsIn the hippocampus, glutamatergic and cholinergic regulation of neuronal excitability is thought to play a pivotal role in learning and memory processes (Pin and

Distinct Subunits in Heteromeric Kainate Receptors Mediate Ionotropic and Metabotropic Function at Hippocampal Mossy Fiber Synapses

“…In CA1 pyramidal cells, the G-protein G␣ q is responsible for the modulation of I sAHP by muscarinic and glutamatergic agonists (Krause et al, 2002). We performed coimmunoprecipitation experiments to determine whether native KARs are associated with G␣ q , using an antibody that recognizes both G␣ q and G␣ 11.…”

Theta-Frequency Synaptic Potentiation in CA1In VitroDistinguishes Cognitively Impaired from Unimpaired Aged Fischer 344 Rats

“…In this regard, basal hippocampal ACh levels in situ are not only reduced in aged F344 rats, but both BIBN-99 and the structurally related M 2 blocker AF DX384 (Ϯ)-5,11 [2,3-b](1,4)-benzodiazepine-6-one) have been shown to elevate hippocampal ACh levels more robustly in aged than young subjects (Quirion et al, 1995;Vannucchi et al, 1997). Blockade of M 2 receptors on ACh terminals could facilitate ACh release and enhance pyramidal cell excitability via diverse postsynaptic mechanisms, including inhibition of the M-current and the sAHP (Brown and Adams, 1980;Pitler and Alger, 1990;Krause and Pedarzani, 2000;Krause et al, 2002). Such actions could enhance complex spike probability (Azouz et al, 1996) and spike propagation into the dendrites (Tsubokawa and Ross, 1997), which is critical to the induction of 5 Hz LTP.…”

Excitatory Roles of Protein Kinase C in Striatal Cholinergic Interneurons

“…Previous studies have demonstrated that activation of group I mGluRs leads to a suppression of several types of potassium currents, including slowly inactivating D-type outward currents (I D ) and apamin-insensitive currents responsible for the slow afterhyperpolarization in hippocampal neurons (Krause et al 2002;Wu and Barish 1999), M-type potassium currents in superior cervical ganglion neurons (Ikeda et al 1995), and 4-AP-sensitive transient currents and 4-AP-insensitive potassium currents in visceral sensory neurons (Hay and Lindsley 1995). In particular, group I mGluRs have been shown to inhibit background potassium currents in cholinergic interneurons, which induces membrane depolarization (Berg et al 2007;Bonsi et al 2005;Takeshita et al 1996).…”