Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory
Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.
View details for DOI 10.1126/science.aan4074
Extended Interneuronal Network of the Dentate Gyrus.
2017; 20 (6): 1262-1268
Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG) to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.
View details for DOI 10.1016/j.celrep.2017.07.042
View details for PubMedID 28793251
View details for PubMedCentralID PMC5576513
Cannabinoid Control of Learning and Memory through HCN Channels
2016; 89 (5): 1059-1073
The mechanisms underlying the effects of cannabinoids on cognitive processes are not understood. Here we show that cannabinoid type-1 receptors (CB1Rs) control hippocampal synaptic plasticity and spatial memory through the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that underlie the h-current (Ih), a key regulator of dendritic excitability. The CB1R-HCN pathway, involving c-Jun-N-terminal kinases (JNKs), nitric oxide synthase, and intracellular cGMP, exerts a tonic enhancement of Ih selectively in pyramidal cells located in the superficial portion of the CA1 pyramidal cell layer, whereas it is absent from deep-layer cells. Activation of the CB1R-HCN pathway impairs dendritic integration of excitatory inputs, long-term potentiation (LTP), and spatial memory formation. Strikingly, pharmacological inhibition of Ih or genetic deletion of HCN1 abolishes CB1R-induced deficits in LTP and memory. These results demonstrate that the CB1R-Ih pathway in the hippocampus is obligatory for the action of cannabinoids on LTP and spatial memory formation.
View details for DOI 10.1016/j.neuron.2016.01.023
View details for PubMedID 26898775
Pass-Through Code of Synaptic Integration.
2015; 87 (6): 1124-1126
How do the components of neuronal circuits collaborate to select combinations of synaptic inputs from multiple pathways? In this issue of Neuron, Milstein et al. (2015) uncover mechanisms of synaptic facilitation and dendritic inhibition that cooperate to provide filtering for co-active inputs of distinct origins.
View details for DOI 10.1016/j.neuron.2015.09.006
View details for PubMedID 26402596
Resolution revolution: epilepsy dynamics at the microscale
CURRENT OPINION IN NEUROBIOLOGY
2015; 31: 239-243
Our understanding of the neuronal mechanisms behind epilepsy dynamics has recently advanced due to the application of novel technologies, monitoring hundreds of neurons with single cell resolution. These developments have provided new theories on the relationship between physiological and pathological states, as well as common motifs for the propagation of paroxysmal activity. Although traditional electroencephalogram (EEG) recordings continue to describe normal network oscillations and abnormal epileptic events within and outside of the seizure focus, analysis of epilepsy dynamics at the microscale has found variability in the composition of macroscopically repetitive epileptiform events. These novel results point to heterogeneity in the underlying dynamics of the disorder, highlighting both the need and potential for more specific and targeted therapies.
View details for DOI 10.1016/j.conb.2014.12.012
View details for Web of Science ID 000352680700034
View details for PubMedID 25596364
Anatomically Heterogeneous Populations of CB1 Cannabinoid Receptor-Expressing Interneurons in the CA3 Region of the Hippocampus Show Homogeneous Input-Output Characteristics
2014; 24 (12): 1506-1523
A subpopulation of GABAergic cells in cortical structures expresses CB1 cannabinoid receptors (CB1 ) on their axon terminals. To understand the function of these interneurons in information processing, it is necessary to uncover how they are embedded into neuronal circuits. Therefore, the proportion of GABAergic terminals expressing CB1 and the morphological and electrophysiological properties of CB1 -immunoreactive interneurons should be revealed. We investigated the ratio and the origin of CB1 -expressing inhibitory boutons in the CA3 region of the hippocampus. Using immunocytochemical techniques, we estimated that ∼40% of GABAergic axon terminals in different layers of CA3 also expressed CB1 . To identify the inhibitory cell types expressing CB1 in this region, we recorded and intracellularly labeled interneurons in hippocampal slices. CB1 -expressing interneurons showed distinct axonal arborization, and were classified as basket cells, mossy-fiber-associated cells, dendritic-layer-innervating cells or perforant-path-associated cells. In each morphological category, a substantial variability in axonal projection was observed. In contrast to the diverse morphology, the active and passive membrane properties were found to be rather similar. Using paired recordings, we found that pyramidal cells displayed large and fast unitary postsynaptic currents in response to activating basket and mossy-fiber-associated cells, while they showed slower and smaller synaptic events in pairs originating from interneurons that innervate the dendritic layer, which may be due to dendritic filtering. In addition, CB1 activation significantly reduced the amplitude of the postsynaptic currents in each cell pair tested. Our data suggest that CB1 -expressing interneurons with different axonal projections have comparable physiological characteristics, contributing to a similar proportion of GABAergic inputs along the somato-dendritic axis of CA3 pyramidal cells.
View details for DOI 10.1002/hipo.22330
View details for Web of Science ID 000345336600010
View details for PubMedID 25044969
Cerebellar Directed Optogenetic Intervention Inhibits Spontaneous Hippocampal Seizures in a Mouse Model of Temporal Lobe Epilepsy.
2014; 1 (1)
Temporal lobe epilepsy is often medically refractory and new targets for intervention are needed. We used a mouse model of temporal lobe epilepsy, on-line seizure detection, and responsive optogenetic intervention to investigate the potential for cerebellar control of spontaneous temporal lobe seizures. Cerebellar targeted intervention inhibited spontaneous temporal lobe seizures during the chronic phase of the disorder. We further report that the direction of modulation as well as the location of intervention within the cerebellum can affect the outcome of intervention. Specifically, on-demand optogenetic excitation or inhibition of parvalbumin-expressing neurons, including Purkinje cells, in the lateral or midline cerebellum results in a decrease in seizure duration. In contrast, a consistent reduction in spontaneous seizure frequency occurs uniquely with on-demand optogenetic excitation of the midline cerebellum, and was not seen with intervention directly targeting the hippocampal formation. These findings demonstrate that the cerebellum is a powerful modulator of temporal lobe epilepsy, and that intervention targeting the cerebellum as a potential therapy for epilepsy should be revisited.
View details for DOI 10.1523/ENEURO.0005-14.2014
View details for PubMedID 25599088
View details for PubMedCentralID PMC4293636
Functional Fission of Parvalbumin Interneuron Classes During Fast Network Events
Fast spiking, parvalbumin (PV) expressing hippocampal interneurons are classified into basket, axo-axonic (chandelier), and bistratified cells. These cell classes play key roles in regulating local circuit operations and rhythmogenesis by releasing GABA in precise temporal patterns onto distinct domains of principal cells. In this study, we show that each of the three major PV cell classes further splits into functionally distinct sub-classes during fast network events in vivo. During the slower (<10 Hz) theta oscillations, each cell class exhibited its own characteristic, relatively uniform firing behavior. However, during faster (>90 Hz) oscillations, within-class differences in PV interneuron discharges emerged, which segregated along specific features of dendritic structure or somatic location. Functional divergence of PV sub-classes during fast but not slow network oscillations effectively doubles the repertoire of spatio-temporal patterns of GABA release available for rapid circuit operations.
View details for DOI 10.7554/eLife.04006
View details for Web of Science ID 000344250100002
View details for PubMedID 25375253
Presynaptic Calcium Channel Inhibition Underlies CB1 Cannabinoid Receptor-Mediated Suppression of GABA Release
JOURNAL OF NEUROSCIENCE
2014; 34 (23): 7958-7963
CB1 cannabinoid receptors (CB1) are located at axon terminals and effectively control synaptic communication and thereby circuit operation widespread in the CNS. Although it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation, the mechanisms of the decrease of GABA release upon activation of these cannabinoid receptors remain elusive. To determine the mechanisms underlying the suppression of synaptic transmission by CB1 at GABAergic synapses, we recorded unitary IPSCs (uIPSCs) at cholecystokinin-expressing interneuron-pyramidal cell connections and imaged presynaptic [Ca(2+)] transients in mouse hippocampal slices. Our results reveal a power function with an exponent of 2.2 between the amplitude of uIPSCs and intrabouton [Ca(2+)]. Altering CB1 function by either increasing endocannabinoid production or removing its tonic activity allowed us to demonstrate that CB1 controls GABA release by inhibiting Ca(2+) entry into presynaptic axon terminals via N-type (Cav2.2) Ca(2+) channels. These results provide evidence for modulation of intrabouton Ca(2+) influx into GABAergic axon terminals by CB1, leading to the effective suppression of synaptic inhibition.
View details for DOI 10.1523/JNEUROSCI.0247-14.2014
View details for Web of Science ID 000337630700022
View details for PubMedID 24899717
The Effects of an Echinacea Preparation on Synaptic Transmission and the Firing Properties of CA1 Pyramidal Cells in the Hippocampus
2012; 26 (3): 354-362
Traditionally, Echinacea preparations are used as antiinflammatory agents and immune-enhancers. In addition to these effects, their anxiolytic potency has been recognized recently in laboratory tests. Our aim in this study was to uncover the potential effects of an Echinacea preparation on neuronal operations in the hippocampus, a brain region that is involved in anxiety and anxiety-related behaviors. Using in vitro electrophysiological techniques, we observed that excitatory synaptic transmission in hippocampal slices was significantly suppressed by an Echinacea extract found to be effective in anxiety tests. In contrast, no change in inhibitory synaptic transmission could be detected upon application of this extract. In addition, our experiments revealed that at low concentration the Echinacea extract reduced the spiking activity of CA1 pyramidal cells, while at high concentration increased it. This latter observation was parallel to the reduction in the magnitude of the h-current-mediated voltage responses in pyramidal cells. At any concentrations, the passive membrane properties of CA1 pyramidal cells were found to be unaltered by the Echinacea extract. In summary, the Echinacea extract can significantly regulate excitatory, but not inhibitory, synaptic transmission in the hippocampus, and this action might be involved in its anxiolytic effects observed in behaviour tests.
View details for DOI 10.1002/ptr.3556
View details for Web of Science ID 000301179300006
View details for PubMedID 21717515
Parvalbumin-Containing Fast-Spiking Basket Cells Generate the Field Potential Oscillations Induced by Cholinergic Receptor Activation in the Hippocampus
JOURNAL OF NEUROSCIENCE
2010; 30 (45): 15134-15145
Gamma frequency oscillations in cortical regions can be recorded during cognitive processes, including attention or memory tasks. These oscillations are generated locally as a result of reciprocal interactions between excitatory pyramidal cells and perisomatic inhibitory interneurons. Here, we examined the contribution of the three perisomatic interneuron types--the parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as the cholecystokinin-containing regular-spiking basket cells (RSBCs) to cholinergically induced oscillations in hippocampal slices, a rhythmic activity that captures several features of the gamma oscillations recorded in vivo. By analyzing the spiking activities of single neurons recorded in parallel with local field potentials, we found that all three cell types fired phase locked to the carbachol-induced oscillations, although with different frequencies and precision. During these oscillations, FSBCs fired the most with the highest accuracy compared with the discharge of AACs and RSBCs. In further experiments, we showed that activation of μ-opioid receptors by DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin acetate), which significantly reduced the inhibitory, but not excitatory, transmission, suppressed or even blocked network oscillations both in vitro and in vivo, leading to the desynchronization of pyramidal cell firing. Using paired recordings, we demonstrated that carbachol application blocked GABA release from RSBCs and reduced it from FSBCs and AACs, whereas DAMGO further suppressed the GABA release only from FSBCs, but not from AACs. These results collectively suggest that the rhythmic perisomatic inhibition, generating oscillatory fluctuation in local field potentials after carbachol treatment of hippocampal slices, is the result of periodic GABA release from FSBCs.
View details for DOI 10.1523/JNEUROSCI.4104-10.2010
View details for Web of Science ID 000284096300029
View details for PubMedID 21068319
Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus
EUROPEAN JOURNAL OF NEUROSCIENCE
2010; 31 (12): 2234-2246
Perisomatic inhibition originates from three types of GABAergic interneurons in cortical structures, including parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as cholecystokinin-expressing regular-spiking basket cells (RSBCs). These interneurons may have significant impact in various cognitive processes, and are subjects of cholinergic modulation. However, it is largely unknown how cholinergic receptor activation modulates the function of perisomatic inhibitory cells. Therefore, we performed paired recordings from anatomically identified perisomatic interneurons and pyramidal cells in the CA3 region of the mouse hippocampus. We determined the basic properties of unitary inhibitory postsynaptic currents (uIPSCs) and found that they differed among cell types, e.g. GABA released from axon endings of AACs evoked uIPSCs with the largest amplitude and with the longest decay measured at room temperature. RSBCs could also release GABA asynchronously, the magnitude of the release increasing with the discharge frequency of the presynaptic interneuron. Cholinergic receptor activation by carbachol significantly decreased the uIPSC amplitude in all three types of cell pairs, but to different extents. M2-type muscarinic receptors were responsible for the reduction in uIPSC amplitudes in FSBC- and AAC-pyramidal cell pairs, while an antagonist of CB(1) cannabinoid receptors recovered the suppression in RSBC-pyramidal cell pairs. In addition, carbachol suppressed or even eliminated the short-term depression of uIPSCs in FSBC- and AAC-pyramidal cell pairs in a frequency-dependent manner. These findings suggest that not only are the basic synaptic properties of perisomatic inhibitory cells distinct, but acetylcholine can differentially control the impact of perisomatic inhibition from different sources.
View details for DOI 10.1111/j.1460-9568.2010.07292.x
View details for Web of Science ID 000279021600012
View details for PubMedID 20529124