Using whole-cell patch-clamp recordings in conjunction with post hoc anatomy we investigated the physiological properties of hippocampal stratum oriens and stratum pyramidale inhibitory interneurones, before and following the induction of pharmacologically evoked gamma frequency network oscillations. Prior to kainate-induced transient epochs of gamma activity, two distinct classes of oriens interneurones, oriens lacunosum-moleculare (O-LM) and trilaminar cells, showed prominent differences in their membrane and firing properties, as well as in the amplitude and kinetics of their excitatory postsynaptic events. In the active network both types of neurone received a phasic barrage of gamma frequency excitatory inputs but, due to their differential functional integration, showed clear differences in their output patterns. While O-LM cells fired intermittently at theta frequency, trilaminar interneurones discharged on every gamma cycle and showed a propensity to fire spike doublets. Two other classes of fast spiking interneurones, perisomatic targeting basket and bistratified cells, in the active network discharged predominantly single action potentials on every gamma cycle. Thus, within a locally excited network, O-LM cells are likely to provide a theta-frequency patterned output to distal dendritic segments, whereas basket and bistratified cells are involved in the generation of locally synchronous gamma band oscillations. The anatomy and output profile of trilaminar cells suggest they are involved in the projection of locally generated gamma rhythms to distal sites. Therefore a division of labour appears to exist whereby different frequencies and spatiotemporal properties of hippocampal rhythms are mediated by different interneurone subtypes.

As a structure involved in learning and memory, the hippocampus functions as a network. The functional differentiation along the longitudinal axis of the hippocampus is poorly demarcated in comparison with the transverse axis. Using patch clamp recordings in conjunction with post hoc anatomy, we have examined the pattern of connectivity and the functional differentiation along the long axis of the hippocampus. Here, we provide anatomical and physiological evidence that the prominent rhythmic network activities of the hippocampus, the behavior-specific gamma and theta oscillations, are seen predominantly along the transverse and longitudinal axes respectively. This orthogonal relationship is the result of the axonal field trajectories and the consequential interaction of the principal cells and major interneuron subtypes involved in generating each rhythm. Thus, the axonal arborization patterns of hippocampal inhibitory cells may represent a structural framework for the spatiotemporal distribution of activity observed within the hippocampus.interneurons ͉ oscillations ͉ patch clamp T he hippocampus is required for the encoding of new information and for retrieving information shortly after acquisition (1). Spatial information is coded at theta frequencies (2) by clusters of neurons segmentally distributed along the longitudinal axis of the hippocampus (3). Gamma oscillations are also generated by the hippocampus nested within these theta rhythms and are thought to be involved in transient neuronal assembly formation (4), information transmission, and storage (5).As previous observation has shown, the hippocampus is made up of multiple lamellae organized in parallel across the long axis, in which each lamella contains a functionally independent transverse circuit (6). The well defined connections between subregions along the transverse axis facilitates the investigation of crucial neurobiological processes such as network oscillatory activity in the in vitro preparation. Although the functionally segregated subregions of the long axis of the hippocampal formation may cooperate with each other during memory formation (for review, see ref. 7), morphological evidence about their interconnectivity is sparse. Although CA3 neurons connect to other CA3 neurons (8, 9), and excitation of interneurons occurs along the longitudinal axis (10), the involvement of hippocampal interneurons in the functional circuit along the longitudinal axis of hippocampus is still unclear.Interneurons serve a wide variety of functions in the brain, amongst them generating and maintaining local or large scale coherent activity (for review, see ref. 11). They also have a particularly pivotal role in driving inhibition-based rhythms, such as gamma and theta frequency network oscillations (12-16). Theta rhythms are seen as a major operational mode of the hippocampus (for review, see ref. 17), and clusters of neurons that encode information required to perform spatial and nonspatial short-term memory tasks during theta rhythms are distributed in di...

Gamma frequency (30 -80 Hz) network oscillations have been observed in the hippocampus during several behavioral paradigms in which they are often modulated by a theta frequency (4 -12 Hz) oscillation. Interneurons of the hippocampus have been shown to be crucially involved in rhythms generation, and several subtypes with distinct anatomy and physiology have been described. In particular, the oriens lacunosum-moleculare (O-LM) interneurons were shown to synapse on distal apical dendrites of pyramidal cells and to spike preferentially at theta frequency, even in the presence of gamma-field oscillations. O-LM cells have also recently been shown to present higher axonal ramification in the longitudinal axis of the hippocampus. By using a hippocampal network model composed of pyramidal cells and two types of interneurons (O-LM and basket cells), we show here that the O-LM interneurons lead to gamma coherence between anatomically distinct cell modules. We thus propose that this could be a mechanism for coupling longitudinally distant cells excited by entorhinal cortex inputs into gamma-coherent assemblies.oscillations ͉ coherence ͉ synchrony ͉ theta rhythm O scillations in cortical structures have been observed in many species (1-3), and among them gamma oscillations (30-80 Hz) have received special attention because of their supposed role in complex functions as sensory binding (2, 3), attention selection (4, 5), and conscious experience (6, 7). Gamma oscillations are prominent in the hippocampus and entorhinal cortex (EC), frequently nested within a theta rhythm (4-12 Hz), and they are thought to be involved in transient neuronal assembly formation (8, 9) and information transmission and storage (10-12). There is compelling evidence that hippocampal interneurons have a pivotal role in driving gamma-and thetafrequency network oscillations (13)(14)(15)(16)(17)(18)(19)(20).GABAergic interneurons present a large morphological and functional heterogeneity in the hippocampal subfields (20)(21)(22). Inhibitory interneurons that control the firing of principal cells include the perisomatic-targeting interneurons (e.g., fast-spiking basket cells) and dendritic-targeting interneurons (20-22). Oriens lacunosum-moleculare (O-LM) interneurons belong to the latter group and are characterized by the cell body and dendritic trees lying horizontally in the stratum oriens, whereas the axon innervates the stratum lacunosum-moleculare (23). The outputs of these cells are projected as slow inhibitory postsynaptic potentials (IPSPs) onto the distal apical dendrites of pyramidal neurons (24). Recently, it was shown that in the CA3 region O-LM interneurons arborize most extensively in the longitudinal axis of the hippocampus (18).Gamma oscillations in the hippocampus can be modulated by theta frequency rhythms both in vivo (25-27) as well as in in vitro (28). This phenomenon may reflect a division of function among interneurons, with the two frequencies generated by distinct subclasses of interneurons. During the gamma rhythm, Gloveli et ...

Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDA-receptor subtype in the aetiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation–inhibition (E/I) balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed.

In central neurons, information flows from the dendritic surface toward the axon terminals. We found that during in vitro gamma oscillations, ectopic action potentials are generated at high frequency in the distal axon of pyramidal cells (PCs) but do not invade the soma. At the same time, axo-axonic cells (AACs) discharged at a high rate and tonically inhibited the axon initial segment, which can be instrumental in preventing ectopic action potential back-propagation. We found that activation of a single AAC substantially lowered soma invasion by antidromic action potential in postsynaptic PCs. In contrast, activation of soma-inhibiting basket cells had no significant impact. These results demonstrate that AACs can separate axonal from somatic activity and maintain the functional polarization of cortical PCs during network oscillations.

The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms. IntroductionResearch has established a solid basis for our understanding of how different nerve cells interact, assemble into functional units, and influence behavior and mood (1-4). High-frequency oscillation of the neuronal membrane potential creates permissive time windows for induction of sensory context-dependent bidirectional plasticity of glutamatergic synaptic transmission (1, 5, 6), which is a synaptic correlate of discriminative associative memory (6-9). Thus, temporal precision of neuronal inputs relative to the actual membrane potential is an important determinant of information coding and memory formation (5, 10-12). GABAergic synaptic transmission is equally relevant for cognitive function, because GABAergic interneurons regulate neuronal excitability and provide a spatiotemporal control framework for the timing of synaptic glutamatergic transmission. Fast-spiking (parvalbumin-positive) interneurons, for example, regulate hippocampal neural network oscillation in cognitively relevant high-gamma frequency ranges (13,14). In conjunction with other interneuron types, they form a precision clockwork without which cortical operations are not possible (15,16). Thus, spatiotemporal coordination of glutamatergic and GABAergic synaptic transmission is essential for sensory processing and cognitive performance.

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Mesial temporal lobe epilepsy (mTLE) is one of the most common forms of epilepsy, characterized by hippocampal sclerosis and memory deficits. Injection of kainic acid (KA) into the dorsal hippocampus of mice reproduces major electrophysiological and histopathological characteristics of mTLE. In extracellular recordings from the morphologically intact ventral hippocampus of KA-injected epileptic mice, we found that theta-frequency oscillations were abolished, whereas gamma oscillations persisted both in vivo and in vitro. Whole-cell recordings further showed that oriens-lacunosum-moleculare (O-LM) interneurons, key players in the generation of theta rhythm, displayed marked changes in their intrinsic and synaptic properties. Hyperpolarization-activated mixed cation currents (Ih) were significantly reduced, resulting in an increase in the input resistance and a hyperpolarizing shift in the resting membrane potential. Additionally, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was increased, indicating a stronger excitatory input to these neurons. As a consequence, O-LM interneurons increased their firing rate from theta to gamma frequencies during induced network activity in acute slices from KA-injected mice. Thus, our physiological data together with network simulations suggest that changes in excitatory input and synaptic integration in O-LM interneurons lead to impaired rhythmogenesis in the hippocampus that in turn may underlie memory deficit.in vitro ͉ interneurons ͉ oscillations ͉ patch-clamp ͉ in vivo