Hippocampal GABAergic cells are highly heterogeneous, but the functional significance of this diversity is not fully understood. By using paired recordings of synaptically connected interneurons in slice preparations of the rat and mouse dentate gyrus (DG), we show that morphologically identified interneurons form complex neuronal networks. Synaptic inhibitory interactions exist between cholecystokinin (CCK)-expressing hilar commissural associational path (HICAP) cells and among somatostatin (SOM)-containing hilar perforant path-associated (HIPP) interneurons. Moreover, both interneuron types inhibit parvalbumin (PV)-expressing perisomatic inhibitory basket cells (BCs), whereas BCs and HICAPs rarely target HIPP cells. HICAP and HIPP cells produce slow, weak, and unreliable inhibition onto postsynaptic interneurons. The time course of inhibitory signaling is defined by the identity of the presynaptic and postsynaptic cell. It is the slowest for HIPP-HIPP, intermediately slow for HICAP-HICAP, but fast for BC-BC synapses. GABA release at interneuroninterneuron synapses also shows cell type-specific short-term dynamics, ranging from multiple-pulse facilitation at HICAP-HICAP, biphasic modulation at HIPP-HIPP to depression at BC-BC synapses. Although dendritic inhibition at HICAP-BC and HIPP-BC synapses appears weak and slow, channelrhodopsin 2-mediated excitation of SOM terminals demonstrates that they effectively control the activity of target interneurons. They markedly reduce the discharge probability but sharpen the temporal precision of action potential generation. Thus, dendritic inhibition seems to play an important role in determining the activity pattern of GABAergic interneuron populations and thereby the flow of information through the DG circuitry.

Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist Nmethyl-D-aspartate (NMDA), and the effects of iron addition/ chelation on hippocampal basal synaptic transmission and longterm potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodinereduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP.Iron deficiency during early life is associated with significantly lower cognitive and behavioral infant development (1-3), severe deterioration of hippocampal neuronal function (4 -6), and poor memory and spatial learning capabilities (7-9). Current understanding of the relationship between neuronal function and brain iron status is sparse, and the molecular mechanisms underlying the essential role of iron in neuronal function remain mostly unidentified. Nonetheless, a role for iron in synaptic plasticity and the associated generation of postsynaptic Ca 2ϩ signals has begun to emerge (10 -12). Neurons obtain iron via transferrin-dependent and -independent uptake pathways. The iron concentration in cerebrospinal fluid is sufficient to saturate the binding capacity of transferrin (13). This feature highlights the need for transferrin-independent iron uptake, which is likely to occur in neurons that express the iron transporter DMT1, such as hippocampal pyramidal and granule cells, cerebellar granule cells, pyramidal cells of the piriform cortex, substantia nigra, and the ventral ...

Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.DOI: http://dx.doi.org/10.7554/eLife.21105.001

Cortical neuronal network operations depend critically on the recruitment of GABAergic interneurons and the properties of their inhibitory output signals. Recent evidence indicates a marked difference in the signalling properties of two major types of perisomatic inhibitory interneurons, the parvalbumin-and the cholecystokinin-containing basket cells. Parvalbumin-expressing basket cells are rapidly recruited by excitatory synaptic inputs, generate high-frequency trains of action potentials, discharge single action potentials phase-locked to fast network oscillations and provide fast, stable and timed inhibitory output onto their target cells. In contrast, cholecystokinin-containing basket cells are recruited in a less reliable manner, discharge at moderate frequencies with single action potentials weakly coupled to the phases of fast network oscillations and generate an asynchronous, fluctuating and less timed inhibitory output. These signalling modes are based on cell type-dependent differences in the functional and plastic properties of excitatory input synapses, integrative qualities and in the kinetics and dynamics of inhibitory output synapses. Thus, the two perisomatic inhibitory interneuron types operate with different speed and precision and may therefore contribute differently to the operations of neuronal networks.

Parvalbumin (PV)-expressing perisoma-inhibiting interneurons (PIIs) of the dentate gyrus integrate rapidly correlated synaptic inputs and generate short-duration action potentials that propagate along the axon to their output synapses, supporting fast inhibitory signaling onto their target cells. Here we show that PV-PIIs in rat and mouse dentate gyrus (DG) integrate their intrinsic activity over time and can turn into a persistent firing mode characterized by the ability to generate long-lasting trains of action potentials at ϳ50 Hz in the absence of additional inputs. Persistent firing emerges in the axons remote from the axon initial segment and markedly depends on hyperpolarization-activated cyclic nucleotide-gated channel (HCNC) activation. Persistent firing properties are modulated by intracellular Ca 2ϩ levels and somatic membrane potential. Detailed computational single-cell PIIs models reveal that HCNC-mediated conductances can contribute to persistent firing during conditions of a shift in their voltage activation curve to more depolarized potentials. Paired recordings from PIIs and their target granule cells show that persistent firing supports strong inhibitory output signaling. Thus, persistent firing may emerge during conditions of intense activation of the network, thereby providing silencing to the circuitry and the maintenance of sparse activity in the dentate gyrus.

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal, pharmacoresistant epilepsy in adults and is often associated with hippocampal sclerosis. Here, we established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for 1 hr resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Finally, acute slice experiments revealed a reduced efficacy of perforant path transmission onto granule cells upon LFS. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE.

Long-term potentiation (LTP) and long-term depression (LTD) are two forms of synaptic plasticity that have been considered as the cellular substrate of memory formation. Although LTP has received considerable more attention, recent evidences indicate that LTD plays also important roles in the acquisition and storage of novel information in the brain. Pannexin 1 (Panx1) is a membrane protein that forms non-selective channels which have been shown to modulate the induction of hippocampal synaptic plasticity. Animals lacking Panx1 or blockade of Pannexin 1 channels precludes the induction of LTD and facilitates LTP. To evaluate if the absence of Panx1 also affects the acquisition of rapidly changing information we trained Panx1 knockout (KO) mice and wild type (WT) littermates in a visual and hidden version of the Morris water maze (MWM). We found that KO mice find the hidden platform similarly although slightly quicker than WT animals, nonetheless, when the hidden platform was located in the opposite quadrant (OQ) to the previous learned location, KO mice spent significantly more time in the previous quadrant than in the new location indicating that the absence of Panx1 affects the reversion of a previously acquired spatial memory. Consistently, we observed changes in the content of synaptic proteins critical to LTD, such as GluN2 subunits of N-methyl-D-aspartate receptors (NMDARs), which changed their contribution to synaptic plasticity in conditions of Panx1 ablation. Our findings give further support to the role of Panx1 channels on the modulation of synaptic plasticity induction, learning and memory processes.

Information processing in cortical neuronal networks relies on properly balanced excitatory and inhibitory neurotransmission. A ubiquitous motif for maintaining this balance is the somatostatin interneuron (SOM-IN) feedback microcircuit. Here, we investigated the modulation of this microcircuit by presynaptic GABAB receptors (GABABRs) in the rodent hippocampus. Whole-cell recordings from SOM-INs revealed that both excitatory and inhibitory synaptic inputs are strongly inhibited by GABABRs, while optogenetic activation of the interneurons shows that their inhibitory output is also strongly suppressed. Electron microscopic analysis of immunogold-labelled freeze-fracture replicas confirms that GABABRs are highly expressed presynaptically at both input and output synapses of SOM-INs. Activation of GABABRs selectively suppresses the recruitment of SOM-INs during gamma oscillations induced in vitro. Thus, axonal GABABRs are positioned to efficiently control the input and output synapses of SOM-INs and can functionally uncouple them from local network with implications for rhythmogenesis and the balance of entorhinal versus intrahippocampal afferents.