A large variety of GABAergic interneurons control information processing in hippocampal circuits governing the formation of neuronal representations. Whether distinct hippocampal interneuron types contribute differentially to information-processing during behavior is not known. We employed a novel technique for recording and labeling interneurons and pyramidal cells in drug-free, freely-moving rats. Recorded parvalbumin-expressing basket interneurons innervate somata and proximal pyramidal cell dendrites, whereas nitric-oxide-synthase-and neuropeptide-Y-expressing ivy cells provide synaptic and extrasynaptic dendritic modulation. Basket and ivy cells showed distinct spike timing dynamics, firing at different rates and times during theta and ripple oscillations. Basket but not ivy cells changed their firing rates during movement, sleep and quiet wakefulness, suggesting that basket cells coordinate cell assemblies in a behavioral state-contingent manner, whereas persistently-firing ivy cells might control network excitability and homeostasis. Different interneuron types provide GABA to specific subcellular domains at defined times and rates, thus differentially controlling network activity during behavior.GABAergic interneurons control information processing in cortical circuits as percussionists set the rhythm for a melody, or traffic lights regulate the movement of cars through a city. Interneurons generate oscillatory activity 1, 2 , synchronize the activity of pyramidal cells 3 and set time windows for synaptic integration 4 . A large diversity of interneuronal types is a hallmark of cortical circuits. Different domains of pyramidal cells, such as the soma, axoninitial-segment, proximal or distal dendrites 5 are innervated by distinct types of GABAergic interneuron. They also have distinct inputs and membrane properties 6-10 and show different firing patterns during network oscillations induced in vitro [11][12][13][14] or recorded in anesthetized animals 15 , indicating distinct roles for specific interneuron types. However, research on interneurons in drug-free animals that can freely change their behavior, has so far been limited to recordings from unidentified interneurons because of technical limitations. In the barrel cortex of head-restrained mice, groups of interneurons with distinct membrane dynamics during different behavioral states have been described 16,17 and in the hippocampus unidentified interneurons or interneurons belonging to heterogeneous groups expressing parvalbumin and/or somatostatin have been reported [18][19][20][21] to fire with different firing patterns during network oscillations. But, how do specific types of identified interneurons control the activity of cortical circuits in freely-moving animals? CouldCorrespondence and requests for materials should be addressed to D.L. (damien.lapray@pharm.ox.ac.uk) Results Identification of neurons recorded in freely-moving ratsWe recorded the activity of parvalbumin (PV)-expressing basket, ivy and pyramidal cells in the dorsal CA...

Cortical gamma oscillations contribute to cognitive processing and are thought to be supported by perisomatic-innervating GABAergic interneurons. We performed extracellular recordings of identified interneurons in the hippocampal CA1 area of anesthetized rats, revealing that the firing patterns of five distinct interneuron types are differentially correlated to spontaneous gamma oscillations. The firing of bistratified cells, which target dendrites of pyramidal cells coaligned with the glutamatergic input from hippocampal area CA3, is strongly phase locked to field gamma oscillations. Parvalbumin-expressing basket, axo-axonic, and cholecystokinin-expressing interneurons exhibit moderate gamma modulation, whereas the spike timing of distal dendrite-innervating oriens-lacunosum moleculare interneurons is not correlated to field gamma oscillations. Cholecystokinin-expressing interneurons fire earliest in the gamma cycle, a finding that is consistent with their suggested function of thresholding individual pyramidal cells. Furthermore, we show that field gamma amplitude correlates with interneuronal spike-timing precision and firing rate. Overall, our recordings suggest that gamma synchronization in vivo is assisted by temporal-and domain-specific GABAergic inputs to pyramidal cells and is initiated in pyramidal cell dendrites in addition to somata and axon initial segments.

Axo-axonic interneurons, innervating exclusively axon initial segments, and parvalbumin-expressing basket interneurons, targeting somata, dendrites, and spines of pyramidal cells, have been proposed to control neuronal activity in prefrontal circuits. We recorded the spike-timing of identified neurons in the prelimbic cortex of anesthetized rats, and show that axo-axonic cells increase their firing during tail pinch-induced brain state-activation. In addition, axo-axonic cells differ from other GABAergic parvalbumin-expressing cells in their spike timing during DOWN-to UP-state transitions of slow oscillations and in their coupling to gamma and spindle oscillations. The distinct firing dynamics and synaptic targets of axo-axonic and other parvalbumin-expressing cells provide differential contributions to the temporal organization of prefrontal networks.

The medial prefrontal cortex is involved in working memory and executive control. However, the collective spatiotemporal organization of the cellular network has not been possible to explain during different brain states. We show that pyramidal cells in the prelimbic cortex fire synchronized to hippocampal theta and local spindle oscillations in anesthetized rats. To identify which types of interneurons contribute to the synchronized activity, we recorded and juxtacellularly labeled parvalbumin-and calbindin-expressing (PVϩ/CBϩ) basket cells and CB-expressing, PV-negative (CBϩ/PVϪ) dendrite-targeting interneurons during both network oscillations. All CBϩ/ PVϪ dendrite-targeting cells strongly decreased their firing rate during hippocampal theta oscillations. Most PVϩ/CBϩ basket cells fired at the peak of dorsal CA1 theta cycles, similar to prefrontal pyramidal cells. We show that pyramidal cells in the ventral hippocampus also fire around the peak of dorsal CA1 theta cycles, in contrast to previously reported dorsal hippocampal pyramidal cells. Therefore, prefrontal neurons might be driven by monosynaptic connections from the ventral hippocampus during theta oscillations. During prefrontal spindle oscillations, the majority of pyramidal cells and PVϩ/CBϩ basket cells fired preferentially at the trough and early ascending phase, but CBϩ/PVϪ dendrite-targeting cells fired uniformly at all phases. We conclude that PVϩ/CBϩ basket cells contribute to rhythmic responses of prefrontal pyramidal cells in relation to hippocampal and thalamic inputs and CBϩ/PVϪ dendrite-targeting cells modulate the excitability of dendrites and spines regardless of these field rhythms. Distinct classes of GABAergic interneuron in the prefrontal cortex contribute differentially to the synchronization of pyramidal cells during network oscillations.

The dentate gyrus (DG) gates neocortical information flow to the hippocampus. Intriguingly, the DG also produces adult-born dentate granule cells (abDGCs) throughout the lifespan, but their contribution to downstream firing dynamics remains unclear. Here, we show that abDGCs promote sparser hippocampal population spiking during mnemonic processing of novel stimuli. By combining triple-(DG-CA3-CA1) ensemble recordings and optogenetic interventions in behaving mice, we show that abDGCs constitute a subset of high-firing-rate neurons with enhanced activity responses to novelty and strong modulation by theta oscillations. Selectively activating abDGCs in their 4–7-week post-birth period increases sparsity of hippocampal population patterns, whereas suppressing abDGCs reduces this sparsity, increases principal cell firing rates and impairs novel object recognition with reduced dimensionality of the network firing structure, without affecting single-neuron spatial representations. We propose that adult-born granule cells transiently support sparser hippocampal population activity structure for higher-dimensional responses relevant to effective mnemonic information processing.

In the hippocampal CA1 area, the GABAergic trilaminar cells have their axon distributed locally in three layers and also innervate the subiculum. Trilaminar cells have a high level of somato-dendritic muscarinic M2 acetylcholine receptor, lack somatostatin expression and their presynaptic inputs are enriched in mGluR8a. But the origin of their inputs and their behaviour-dependent activity remain to be characterised. Here we demonstrate that (1) GABAergic neurons with the molecular features of trilaminar cells are present in CA1 and CA3 in both rats and mice. (2) Trilaminar cells receive mGluR8a-enriched GABAergic inputs, e.g. from the medial septum, which are probably susceptible to hetero-synaptic modulation of neurotransmitter release by group III mGluRs. (3) An electron microscopic analysis identifies trilaminar cell output synapses with specialised postsynaptic densities and a strong bias towards interneurons as targets, including parvalbumin-expressing cells in the CA1 area. (4) Recordings in freely moving rats revealed the network state-dependent segregation of trilaminar cell activity, with reduced firing during movement, but substantial increase in activity with prolonged burst firing (> 200 Hz) during slow wave sleep. We predict that the behaviour-dependent temporal dynamics of trilaminar cell firing are regulated by their specialised inhibitory inputs. Trilaminar cells might support glutamatergic principal cells by disinhibition and mediate the binding of neuronal assemblies between the hippocampus and the subiculum via the transient inhibition of local interneurons.

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Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing pyramidal cells, with the remaining cells retaining their coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely-moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms implementing cortical neuronal coordination compensate for the widespread pTau aggregation, loss of high-firing cells and neurodegeneration.