Differential sensitivity to Zolpidem of IPSPs activated by morphologically identified CA1 interneurons in slices of rat hippocampus

Abstract

Hippocampal pyramidal cells express several alpha-subunits, which determine the affinity of GABAA (gamma-aminobutyric acid) receptors for benzodiazepine site ligands. This study asked whether inhibitory postsynaptic potentials (IPSPs) elicited by specific interneuronal subclasses were differentially sensitive to the alpha1-preferring agonist Zolpidem, i.e. whether different receptors mediate different inhibitory connections. Paired intracellular recordings in which the presynaptic cell was an interneuron and the postsynaptic cell a CA1 pyramid were performed in slices of adult rat hippocampus. Resultant IPSPs were challenged with Zolpidem, cells filled with biocytin and identified morphologically. IPSPs elicited by fast spiking (FS) basket cells (n = 9) were enhanced more than IPSPs elicited by regular spiking (RS) basket cells (n = 10). At FS basket cell synapses the efficacy of Zolpidem was equivalent to that of Diazepam, while RS basket cell IPSPs are enhanced 50% less by Zolpidem than by Diazepam. Thus, while alpha1 subunits may dominate at synapses supplied by FS basket cells, RS basket cell synapses also involve alpha2/3 subunits. Two bistratified cell IPSPs tested with Zolpidem did not increase in amplitude, despite powerful enhancements of bistratified cell IPSPs by Diazepam, consistent with previous indications that these synapses utilize alpha5-containing receptors. Enhancements of basket cell IPSPs by Zolpidem and Diazepam were bi- or triphasic with steep amplitude increases separated by plateaux, occurring 10-15, 25-30 and 45-55 min after adding the drug to the bath. The entire enhancement was, however, blocked by the antagonist Flumazenil (n = 7). Flumazenil, either alone (n = 3), or after Zolpidem, reduced IPSP amplitude to approximately 90% of control, suggesting that alpha4-containing receptors were not involved.

Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABA_A Receptors

“…The α3-GABA A Rs are located in perisomatic regions of medium spiny neurons and are contacted by local GP axon collaterals, whilst the α2-GABA A Rs are located on distal dendrites of these neurons and contacted primarily by inputs from the striatum 32 . Expression of specific α subunits in different types of synapses and in different neuronal compartments has also been demonstrated in other brain areas such as hippocampus 21 and neocortex 18,20 . These findings raise the question as to how the specific inhibitory synapses are formed in the brain.…”

“…Evidence indicates that GABAergic synapse development is a precisely co-ordinated sequence of events, in which both the neuronal targets contacted by different types of inhibitory axons and the receptors that are clustered at each class of inhibitory synapse are selective and functionally attuned 17,[20][21][22] . This fundamental principle of specificity at GABAergic synapses raises the question as to how the pre-and postsynaptic partners recognize each other during the initiation of synaptic contacts.…”

α5GABAAReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

“…The distribution of ␣5GABA A Rs in pyramidal neurons is non-uniform, with the highest expression levels found in the dendritic regions of the hippocampal subfields, a region that is targeted by dendritic-targeting bistratified interneurons (Thomson et al, 2000;Klausberger and Somogyi, 2008). Interestingly, the application of THIP to Gabra5 Ϫ/Ϫ slices increased the residual tonic conductance and blocked LTP but failed to mimic the LTD seen in WT slices.…”

Postnatal Differentiation of Basket Cells from Slow to Fast Signaling Devices

“…6 D). At low concentrations, Zolpidem selectively affects GABA A receptors assembled from ␣1␤␥2 subunits (Thomson et al, 2000;Cope et al, 2005). The addition of 5 M Zolpidem to the bath solution significantly increased w of compound IPSCs evoked by extracellular stimulation in the GC layer in mature cells (159.6 Ϯ 36%; six cells), indicating the presence of ␣1 subunits.…”