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Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

ABSTRACT: Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV⁺) and somatostatin-expressing (SST⁺), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV⁺ and SST⁺ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV⁺ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST⁺ interneurons has the opposite effect. Thus, DG and CA3 PV⁺ and SST⁺ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

SUBMITTER: Aery Jones EA

PROVIDER: S-EPMC9069800 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

Aery Jones Emily A EA Rao Antara A Zilberter Misha M Djukic Biljana B Bant Jason S JS Gillespie Anna K AK Koutsodendris Nicole N Nelson Maxine M Yoon Seo Yeon SY Huang Ky K Yuan Heidi H Gill Theodore M TM Huang Yadong Y Frank Loren M LM

Cell reports 20211201 13

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ int ...[more]

PMID: 34965435

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Project description:The medial septum implements cortical theta oscillations, a 5-12 Hz rhythm associated with locomotion and paradoxical sleep reflecting synchronization of neuronal assemblies such as place cell sequence coding. Highly rhythmic burst-firing parvalbumin-positive GABAergic medial septal neurons are strongly coupled to theta oscillations and target cortical GABAergic interneurons, contributing to coordination within one or several cortical regions. However, a large population of medial septal neurons of unidentified neurotransmitter phenotype and with unknown axonal target areas fire with a low degree of rhythmicity. We investigated whether low-rhythmic-firing neurons (LRNs) innervated similar or different cortical regions to high-rhythmic-firing neurons (HRNs) and assessed their temporal dynamics in awake male mice. The majority of LRNs were GABAergic and parvalbumin-immunonegative, some expressing calbindin; they innervated interneurons mostly in the dentate gyrus (DG) and CA3. Individual LRNs showed several distinct firing patterns during immobility and locomotion, forming a parallel inhibitory stream for the modulation of cortical interneurons. Despite their fluctuating firing rates, the preferred firing phase of LRNs during theta oscillations matched the highest firing probability phase of principal cells in the DG and CA3. In addition, as a population, LRNs were markedly suppressed during hippocampal sharp-wave ripples, had a low burst incidence, and several of them did not fire on all theta cycles. Therefore, CA3 receives GABAergic input from both HRNs and LRNs, but the DG receives mainly LRN input. We propose that distinct GABAergic LRNs contribute to changing the excitability of the DG and CA3 during memory discrimination via transient disinhibition of principal cells.SIGNIFICANCE STATEMENT For the encoding and recall of episodic memories, nerve cells in the cerebral cortex are activated in precisely timed sequences. Rhythmicity facilitates the coordination of neuronal activity and these rhythms are detected as oscillations of different frequencies such as 5-12 Hz theta oscillations. Degradation of these rhythms, such as through neurodegeneration, causes memory deficits. The medial septum, a part of the basal forebrain that innervates the hippocampal formation, contains high- and low-rhythmic-firing neurons (HRNs and LRNs, respectively), which may contribute differentially to cortical neuronal coordination. We discovered that GABAergic LRNs preferentially innervate the dentate gyrus and the CA3 area of the hippocampus, regions important for episodic memory. These neurons act in parallel with the HRNs mostly via transient inhibition of inhibitory neurons.

Project description:BackgroundPathophysiological evidence from temporal lobe epilepsy models highlights the hippocampus as the most affected structure due to its high degree of neuroplasticity and control of the dynamics of limbic structures, which are necessary to encode information, conferring to it an intrinsic epileptogenicity. A loss in this control results in observable oscillatory perturbations called fast ripples, in epileptic rats those events are found in CA1, CA3, and the dentate gyrus (DG), which are the principal regions of the trisynaptic circuit of the hippocampus. The present work used Granger causality to address which relationships among these three regions of the trisynaptic circuit are needed to cause fast ripples in CA1 in an in vivo model. For these purposes, male Wistar rats (210-300 g) were injected with a single dose of pilocarpine hydrochloride (2.4 mg/2 µl) into the right lateral ventricle and video-monitored 24 h/day to detect spontaneous and recurrent seizures. Once detected, rats were implanted with microelectrodes in these regions (fixed-recording tungsten wire electrodes, 60-μm outer diameter) ipsilateral to the pilocarpine injection. A total of 336 fast ripples were recorded and probabilistically characterized, from those fast ripples we made a subset of all the fast ripple events associated with sharp-waves in CA1 region (n = 40) to analyze them with Granger Causality.ResultsOur results support existing evidence in vitro in which fast ripple events in CA1 are initiated by CA3 multiunit activity and describe a general synchronization in the theta band across the three regions analyzed DG, CA3, and CA1, just before the fast ripple event in CA1 have begun.ConclusionThis in vivo study highlights the causal participation of the CA3 back-projection to the DG, a connection commonly overlooked in the trisynaptic circuit, as a facilitator of a closed-loop among these regions that prolongs the excitatory activity of CA3. We speculate that the loss of inhibitory drive of DG and the mechanisms of ripple-related memory consolidation in which also the CA3 back-projection to DG has a fundamental role might be underlying processes of the fast ripples generation in CA1.

Dataset Information

Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

Publications

Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

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