A1 adenosine receptor-mediated GIRK channels contribute to the resting conductance of CA1 neurons in the dorsal hippocampus.

The dorsal and ventral hippocampi are functionally and anatomically distinct. Recently, we reported that dorsal Cornu Ammonis area 1 (CA1) neurons have a more hyperpolarized resting membrane potential and a lower input resistance and fire fewer action potentials for a given current injection than ventral CA1 neurons. Differences in the hyperpolarization-activated cyclic nucleotide-gated cation conductance between dorsal and ventral neurons have been reported, but these differences cannot fully account for the different resting properties of these neurons. Here, we show that coupling of A1 adenosine receptors (A1ARs) to G-protein-coupled inwardly rectifying potassium (GIRK) conductance contributes to the intrinsic membrane properties of dorsal CA1 neurons but not ventral CA1 neurons. The block of GIRKs with either barium or the more specific blocker Tertiapin-Q revealed that there is more resting GIRK conductance in dorsal CA1 neurons compared with ventral CA1 neurons. We found that the higher resting GIRK conductance in dorsal CA1 neurons was mediated by tonic A1AR activation. These results demonstrate that the different resting membrane properties between dorsal and ventral CA1 neurons are due, in part, to higher A1AR-mediated GIRK activity in dorsal CA1 neurons.

Kim CS ，Johnston D 《-》

GABA(B) receptors in neocortical and hippocampal pyramidal neurons are coupled to different potassium channels.

Classically, GABAB receptors are thought to regulate neuronal excitability via G-protein-coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABAB receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABAB receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 μm) abolished outward currents evoked by GABAB receptors in CA1 pyramidal, but only partially blocked GABAB responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin-Q, a specific GIRK channel blocker. Tertiapin-Q partially blocked GABAB responses in CA1 pyramidal neurons, but was ineffective in blocking GABAB responses in neocortical layer 5 neurons. Consistent with the idea that GABAB receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABAB responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABAB responses mediated by two-pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABAB receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABAB inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity.

Breton JD ，Stuart GJ 《-》

Dendritic GIRK Channels Gate the Integration Window, Plateau Potentials, and Induction of Synaptic Plasticity in Dorsal But Not Ventral CA1 Neurons.

Studies comparing neuronal activity at the dorsal and ventral poles of the hippocampus have shown that the scale of spatial information increases and the precision with which space is represented declines from the dorsal to ventral end. These dorsoventral differences in neuronal output and spatial representation could arise due to differences in computations performed by dorsal and ventral CA1 neurons. In this study, we tested this hypothesis by quantifying the differences in dendritic integration and synaptic plasticity between dorsal and ventral CA1 pyramidal neurons of rat hippocampus. Using a combination of somatic and dendritic patch-clamp recordings, we show that the threshold for LTP induction is higher in dorsal CA1 neurons and that a G-protein-coupled inward-rectifying potassium channel mediated regulation of dendritic plateau potentials and dendritic excitability underlies this gating. By contrast, similar regulation of LTP is absent in ventral CA1 neurons. Additionally, we show that generation of plateau potentials and LTP induction in dorsal CA1 neurons depends on the coincident activation of Schaffer collateral and temporoammonic inputs at the distal apical dendrites. The ventral CA1 dendrites, however, can generate plateau potentials in response to temporally dispersed excitatory inputs. Overall, our results highlight the dorsoventral differences in dendritic computation that could account for the dorsoventral differences in spatial representation.SIGNIFICANCE STATEMENT The dorsal and ventral parts of the hippocampus encode spatial information at very different scales. Whereas the place-specific firing fields are small and precise at the dorsal end of the hippocampus, neurons at the ventral end have comparatively larger place fields. Here, we show that the dorsal CA1 neurons have a higher threshold for LTP induction and require coincident timing of excitatory synaptic inputs for the generation of dendritic plateau potentials. By contrast, ventral CA1 neurons can integrate temporally dispersed inputs and have a lower threshold for LTP. Together, these dorsoventral differences in the threshold for LTP induction could account for the differences in scale of spatial representation at the dorsal and ventral ends of the hippocampus.

Malik R ，Johnston D 《-》

Constitutively active G-protein-gated inwardly rectifying K+ channels in dendrites of hippocampal CA1 pyramidal neurons.

Chen X ，Johnston D 《-》

Role of A(1) receptor-activated GIRK channels in the suppression of hippocampal seizure activity.

The neuromodulator adenosine is released during seizure activity to provide negative feedback suppression of ongoing activity and to delay the occurrence of the next burst of activity. Adenosine acts via multiple G-protein-coupled receptors including the A1 receptor (A1R) which inhibits neurotransmitter release and hyperpolarises neuronal membrane potential. The hyperpolarisation is produced, at least in part, by the activation of G-protein-activated inwardly rectifying K+ (GIRK) channels. We have used tertiapin-Q (TQ), a potent and selective inhibitor of GIRK channels, to assess the role of GIRK channels in controlling seizure activity in areas CA1 and CA2 of mouse hippocampal slices. TQ (100-300 nM) blocked ~50% of the adenosine-mediated membrane potential hyperpolarisation of hippocampal CA1 and CA2 neurons. TQ (100 nM) had no significant effect on synaptic transmission in area CA1 of the hippocampus but enhanced transmission in CA2, an effect prevented by blocking A1Rs. TQ (100 nM) increased the frequency of spontaneous activity (induced by removing Mg2+ and increasing K+) and blunted the effects of exogenous adenosine on the suppression of activity. TQ had a significantly greater effect on electrically-stimulated seizure activity induced in CA2 versus that in CA1, producing a greater increase in both the duration and amplitude of the stimulated bursts. This is consistent with the greater A1R density and A1R activation tone in CA2. Thus GIRK channels play a role in the supressing effects of adenosine on seizure activity.

Hill E ，Hickman C ，Diez R ，Wall M ... -  《-》