Hippocampal GABAergic interneurons show diverse molecular and morphological properties. The functional significance of this diversity for information processing is poorly understood. Here we show that cholecystokinin (CCK)-expressing interneurons in rat dentate gyrus release GABA in a highly asynchronous manner, in contrast to parvalbumin (PV) interneurons. With a gamma-frequency burst of ten action potentials, the ratio of asynchronous to synchronous release is 3:1 in CCK interneurons but is 1:5 in parvalbumin interneurons. N-type channels trigger synchronous and asynchronous release in CCK interneuron synapses, whereas P/Q-type Ca(2+) channels mediate release at PV interneuron synapses. Effects of Ca(2+) chelators suggest that both a long-lasting presynaptic Ca(2+) transient and a large distance between Ca(2+) source and sensor of exocytosis contribute to the higher ratio of asynchronous to synchronous release in CCK interneuron synapses. Asynchronous release occurs at physiological temperature and with behaviorally relevant stimulation patterns, thus generating long-lasting inhibition in the brain.

In many species, spatial navigation is supported by a network of place cells that exhibit increased firing whenever an animal is in a certain region of an environment. Does this neural representation of location form part of the spatiotemporal context into which episodic memories are encoded? We recorded medial temporal lobe neuronal activity as epilepsy patients performed a hybrid spatial and episodic memory task. We identified place-responsive cells active during virtual navigation and then asked whether the same cells activated during the subsequent recall of navigation-related memories without actual navigation. Place-responsive cell activity was reinstated during episodic memory retrieval. Neuronal firing during the retrieval of each memory was similar to the activity that represented the locations in the environment where the memory was initially encoded.

SUMMARYPurpose: c-Aminobutyric acid (GABA)ergic transmission plays an important role in the initiation of epileptic activity and the generation of ictal discharges. The functional alterations in the epileptiform hippocampus critically depend on GABAergic mechanisms and cation-chloride cotransporters. Methods: To understand the cellular basis of specific functional alterations in the epileptic hippocampus, we studied physiologic characteristics and pharmacologically isolated evoked GABA A receptor-mediated inhibitory postsynaptic currents (IPSCs) recorded from principal neurons in hippocampal slices from status epilepticus (SE) and control rats using whole-cell and gramicidin perforated patch-clamp recordings. Key Findings: Whereas the resting membrane potential and input resistance were not significantly different between control and epileptic tissue, the reversal potential (E GABA ) of IPSCs was significantly shifted to more positive values in SE rats with regard to the resting membrane potential. Pharmacologic experiments and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) showed that the observed changes in the epileptic tissue were due to a decreased ratio of the main Cl) cotransporter, NKCC1). Significance: Our results suggest that alterations of cation-chloride cotransporter functions, comprising a higher NKCC1 action, contribute to hyperexcitability within the hippocampus following SE.

Despite its predominant role in the peripheral nervous system and particularly at the motor endplate where it was first discovered, fast nicotinic cholinergic transmission has been found up to now only exceptionally in the central nervous system. One classic example is the synaptic activation of the Renshaw cell in the spinal cord, which receives a cholinergic nicotinic input from motoneurones (Eccles et al. 1954). Similarly, synaptic nicotinic potentials have been reported in brainstem vagal motoneurones (Zhang et al. 1993) and neuronal nicotinic acetylcholine receptor (nAChR) mediated responses could at least in part mediate dopamine release in the striatum (Clarke et al. 1987; Futami et al. 1995). So far, however, there has been no report of fast cholinergic transmission in mammalian cortical regions. Contrasting with this, nicotine has been shown to play a major role in modulating brain functions (Wonnacott, 1997). Recent developments in gene technology have revealed the presence in many brain areas of mRNA coding for different nicotinic receptor subtypes (Goldman et al. 1987;Sargent, 1993). Furthermore, the presence of these mRNAs correlates well with reports of the existence of specific binding sites for both ACh analogues and the selective nicotinic receptor antagonist á_bungarotoxin (á-BgTX;Clarke et al. 1985). In addition, electrophysiological studies made on dissociated hippocampal neurones have demonstrated the existence of functional nicotinic receptors and identified several types of nicotinic currents (Alkondon & Albuquerque, 1993; Albuquerque et al. 1997). Finally, strong evidence implicates nicotinic acetylcholine receptors in behaviour, learning and memory as well as in the reinforcing actions of nicotine (Role & Berg, 1996;Picciotto et al. 1998). A major issue, therefore, has been to understand whether neuronal nAChRs have purely a modulatory role, representing mainly targets for the low concentrations of nicotine that reach the brain during smoking, or whether, as found in the peripheral nervous system, they also mediate fast synaptic transmission. This is not unlikely considering the evidence showing the existence in the hippocampus of a

To examine possible interactions between fast depression and modulation of inhibitory synaptic transmission in the hippocampus, we recorded from pairs of synaptically connected basket cells (BCs) and granule cells (GCs) in the dentate gyrus of rat brain slices at 34 °C. Multiple‐pulse depression (MPD) was examined in trains of 5 or 10 inhibitory postsynaptic currents (IPSCs) evoked at frequencies of 10–00 Hz under several conditions that inhibit transmitter release: block of voltage‐dependent Ca2+ channels by Cd2+ (10 μm), activation of γ‐amino‐butyric acid type B receptors (GABABRs) by baclofen (10 μm) and activation of muscarinic acetylcholine receptors (mAchRs) by carbachol (2 μm). All manipulations led to a substantial inhibition of synaptic transmission, reducing the amplitude of the first IPSC in the train (IPSC1) by 72 %, 61 % and 29 %, respectively. However, MPD was largely preserved under these conditions (0.34 in control versus 0.31, 0.50 and 0.47 in the respective conditions at 50 Hz). Similarly, a theta burst stimulation (TBS) protocol reduced IPSC1 by 54 %, but left MPD unchanged (0.40 in control and 0.39 during TBS). Analysis of both fractions of transmission failures and coefficients of variation (CV) of IPSC peak amplitudes suggested that MPD had a presynaptic expression site, independent of release probability. In conclusion, different types of presynaptic modulation of inhibitory synaptic transmission converge on a reduction of synaptic strength, while short‐term dynamics are largely unchanged.