Dual intracellular recordings in the CA1 region of adult rat hippocampal slices and biocytin filling of synaptically connected cells were used to study the excitatory postsynaptic potentials (EPSPs) elicited in basket (n= 7) and bistratified interneurones (n= 7) by action potentials activated in simultaneously recorded pyramidal cells. Interneurones could be subdivided according to their electrophysiological properties into classical fast spiking, burst firing, regular spiking and fast spiking cells with a rounded spike after‐hyperpolarization. These physiological classes did not, however, correlate with morphological type. EPSPs were not recorded in regular spiking cells. Average EPSP amplitudes were larger in bistratified cells (range, 0.5–9 mV) than in basket cells (range, 0.15–3.6 mV) and the probability of obtaining a pyramidal cell‐interneurone EPSP was also higher for the bistratified cells (1:7) than for the basket cells (1:22). EPSP 10–90% rise times in bistratified cells (0.7–2 ms) and their widths at half‐amplitude (3.9–11.2 ms) were slightly longer than in basket cells (rise times, 0.4–1.6 ms; half‐widths, 2.2–9.7 ms). The majority of these EPSPs (6 of 8 tested) increased in amplitude and duration with postsynaptic depolarization, although in two (of 4) basket cells the voltage relation was conventional. All EPSPs tested in both basket (n= 7) and bistratified cells (n= 5) decreased in amplitude with repetitive presynaptic firing. The average amplitudes of second EPSPs elicited within 15 ms of the first were between 34 and 94% of the average amplitude of the first EPSP. Third and fourth EPSPs in brief trains were further depressed. This depression was associated with an increase in the incidence of apparent failures of transmission indicating a presynaptic locus.

Previous studies indicated that one class of dendrite-preferring hippocampal interneurones inhibits pyramidal cells via a5 gaminobutyric acid (GABA A ) receptors whereas parvalbumin-and CCK-containing basket cells act via a1 and a2/3 GABA A receptors, respectively. This study asked whether there is selective insertion of different a subunit--containing GABA A receptors at neocortical inhibitory synapses innervated by specific classes of interneurones. The benzodiazepine site pharmacology of inhibitory postsynaptic potentials (IPSPs) elicited in neocortical pyramidal cells by 3 classes of interneurones was explored with dual whole-cell recordings in neocortical slices from juvenile rats (P18--23). Fast IPSPs activated by multipolar interneurones with narrow spikes and nonadapting firing patterns were powerfully enhanced by the a1-preferring agonist zolpidem, suggesting mediation via larger proportion of a1 GABA A receptors than those activated by multipolar, adapting interneurones, which were less strongly enhanced by zolpidem, but equally insensitive to the a5-selective inverse agonist IAalpha5 (MSD, Essex, UK) suggesting mediation predominantly via a2/3 GABA A receptors. In contrast, the IPSPs elicited by bitufted, dendrite-preferring interneurones were reduced by IAalpha5 and by zinc and insensitive to zolpidem despite enhancement by the broad-spectrum agonist, diazepam. Thus insertion of GABA A receptors at synapses on neocortical pyramids is input-specific, with proximal inhibition employing a1 and a2/3 GABA A receptors and dendrite-preferring bitufted interneurones activating a5 GABA A receptors.

In adult rat hippocampal slices, simultaneous intracellular recordings from pyramidal cells in CA1 and interneurones near the stratum oriens‐alveus border revealed excitatory connections that displayed facilitation on repetitive activation in twelve of thirty‐six pairs tested. Postsynaptic interneurones were classified as horizontal oriens‐alveus interneurones by the pronounced ‘sag’ in response to hyperpolarizing current injection, high levels of spontaneous synaptic activity and by the morphology of their somata and dendrites, which were confined to stratum oriens‐alveus and their axons which projected to stratum lacunosum‐moleculare where they ramified extensively, in the region of entorhinal cortex input to CA1. Excitatory postsynaptic potentials (EPSPs) elicited by single pyramidal cells were 0 to 12 mV in amplitude. Mean EPSP amplitude (single spikes) was 0.93 ± 1.06 mV at −70 ± 2.3 mV (n= 10). The rise time was 1.2 ± 0.5 ms and the width at half‐amplitude was 7.5 ± 4.7 ms. EPSPs fluctuated greatly in amplitude; the mean coefficient of variation was 0.84 ± 0.37 for the first EPSP and 0.47 ± 0.24 for the second. Apparent failures of transmission frequently occurred after first presynaptic spikes but less frequently after the second or subsequent spikes in brief trains. EPSPs displayed facilitation at membrane potentials between −80 mV and spike threshold. Second EPSPs within 20 ms of the first were 253 ± 48% (range, 152–324%) of the mean first EPSP amplitude. Third EPSPs within 60 ms were 266 ± 70 % (range, 169–389%) and fourth EPSPs within 60–120 ms were 288 ± 71% (range, 188–393%). Both proportions of apparent failures of transmission and coefficient of variation analysis indicated a presynaptic locus for this facilitation.

Synaptic dysfunction is widely proposed as an initial insult leading to the neurodegeneration observed in Alzheimer’s disease (AD). We hypothesize that the initial insult originates in the lateral entorhinal cortex (LEC) due to deficits in key interneuronal functions and synaptic signaling mechanisms, in particular, Wnt (Wingless/integrated). To investigate this hypothesis, we utilized the first knock-in mouse model of AD (AppNL-F/NL-F), expressing a mutant form of human amyloid-β (Aβ) precursor protein. This model shows an age-dependent accumulation of Aβ, neuroinflammation, and neurodegeneration. Prior to the typical AD pathology, we showed a decrease in canonical Wnt signaling activity first affecting the LEC in combination with synaptic hyperexcitation and severely disrupted excitatory–inhibitory inputs onto principal cells. This synaptic imbalance was consistent with a reduction in the number of parvalbumin-containing (PV) interneurons, and a reduction in the somatic inhibitory axon terminals in the LEC compared with other cortical regions. However, targeting GABAA receptors on PV cells using allosteric modulators, diazepam, zolpidem, or a nonbenzodiazepine, L-838,417 (modulator of α2/3 subunit-containing GABAA receptors), restored the excitatory–inhibitory imbalance observed at principal cells in the LEC. These data support our hypothesis, providing a rationale for targeting the synaptic imbalance in the LEC for early stage therapeutic intervention to prevent neurodegeneration in AD.

The influence of local circuit interneurons is thought to play an important role in adjusting synaptic strength via endogenous cannabinoid type 1 (CB1) receptors. Using paired whole-cell recordings, combined with double immunofluorescence and biocytin labelling in acute slices of rat CA1 at postnatal day 18-23, we investigated the properties of Cholecystokinin (CCK)-positive stratum radiatum local circuit interneuron connections that utilised CB1 receptors. Three types of synaptic connections were studied, lacunosum-moleculare-radiatum perforant path-associated (LM-R PPA) to Shaffer collateral-associated (SCA) interneurons, SCA-SCA interneurons and SCA-pyramidal cells. These three synapses were differentially under tonic reduction of inhibition that was blocked by the CB1 receptor inverse agonist AM-251 (10 lm), which enhanced IPSPs. The strength of tonic reduction of inhibition was correlated with asynchronous release which was apparent at connections among interneurons. AM-251 increased the ratio of synchronous to asynchronous release (synchronicity ratio), while the CB receptor agonist anandamide (14 lm) decreased the synchronicity ratio. Fast and slow calcium chelators (BAPTA-AM and EGTA-AM) also increased the synchronicity ratio, accelerated inhibitory time courses and reduced IPSP amplitudes. These data suggest that CB1 receptors at connections among interneuron synapses play a role in tonic suppression of inhibition and govern the asynchronous release of GABA, modulating the time windows of inhibition. Effects of calcium chelators suggest that asynchronous release is a result of a long-lasting presynaptic calcium transients and ⁄ or a large distance between calcium source and sensor of exocytosis. These properties of specialised inhibitory neurons may have important modulatory roles in controlling spike timing among local circuit interneurons.