Subicular Neurons Research Articles

Human subiculo-fornico-mamillary system in Alzheimer's disease: Tau seeding by the pillar of the fornix.

In Alzheimer's disease (AD), Tau and Aβ aggregates involve sequentially connected regions, sometimes distantly separated. These alterations were studied in the pillar of the fornix (PoF), an axonal tract, to analyse the role of axons in their propagation. The PoF axons mainly originate from the subicular neurons and project to the mamillary body. Forty-seven post-mortem cases at various Braak stages (Tau) and Thal phases (Aβ) were analysed by immunohistochemistry. The distribution of the lesions showed that the subiculum was affected before the mamillary body, but neither Tau aggregation nor Aβ deposition was consistently first. The subiculum and the mamillary body contained Gallyas positive neurofibrillary tangles, immunolabelled by AT8, TG3, PHF1, Alz50 and C3 Tau antibodies. In the PoF, only thin and fragmented threads were observed, exclusively in the cases with neurofibrillary tangles in the subiculum. The threads were made of Gallyas negative, AT8 and TG3 positive Tau. They were intra-axonal and devoid of paired helical filaments at electron microscopy. We tested PoF homogenates containing Tau AT8 positive axons in a Tau P301S biosensor HEK cell line and found a seeding activity. There was no Aβ immunoreactivity detected in the PoF. We could follow microcryodissected AT8 positive axons entering the mamillary body; contacts between Tau positive endings and Aβ positive diffuse or focal deposits were observed in CLARITY-cleared mamillary body. In conclusion, we show that non-fibrillary, hyperphosphorylated Tau is transported by the axons of the PoF from the subiculum to the mamillary body and has a seeding activity. Either Tau aggregation or Aβ accumulation may occur first in this system: this inconstant order is incompatible with a cause-and-effects relationship. However, both pathologies were correlated and intimately associated, indicating an interaction of the two processes, once initiated.

Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model.

Much evidence suggests that the subiculum plays a significant role in the regulation of epileptic activity. Lactate acts as a neuroprotective agent against many conditions that cause brain damage. During epileptic seizures, lactate formation reaches up to ~6mmol/L in the brain. We investigated the effect of lactate on subicular pyramidal neurons after induction of epileptiform activity using 4-aminopyridine (4-AP-0Mg2+ ) in an in vitroepilepsy model in rats. The signaling mechanism associated with the suppression of epileptiform discharges by lactate was also investigated. We used patch clamp electrophysiology recordings on rat subicular neurons of acute hippocampal slices. Immunohistochemistry was used for demonstrating the expression of hydroxycarboxylic acid receptor 1 (HCA1) in the subiculum. Our study showed that application of 6mmol/L lactate after induction of epileptiform activity reduced spike frequency (control 2.5±1.23Hz vs lactate 1.01±0.91Hz, P=.049) and hyperpolarized the subicular neurons (control -51.8±1.9mV vs lactate -57.2±3.56mV, P=.002) in whole cell patch-clamp experiments. After confirming the expression of HCA1 in subicular neurons, we demonstrated that lactate-mediated effect occurs via HCA1 by using its specific agonist. All values are mean ±SD.Electrophysiological recordings revealed the involvement of Gβγ and intracellular cAMP in the lactate-induced effect. Furthermore, current-clamp and voltage-clamp experiments showed that the G protein-coupled inwardly rectifying potassium (GIRK) channel blocker tertiapin-Q, negated the lactate-induced inhibitory effect, which confirmed that lactate application results in outward GIRK current. Our finding points toward the potential role of lactate as an anticonvulsant by showing lactate-induced suppression of epileptiform activity in subicular neurons. The study gives a different insight by suggesting importance of endogenous metabolite and associated signaling factors, which can aid in improving the present therapeutic approach for treating epilepsy.

Amyloid pathology–produced unexpected modifications of calcium homeostasis in hippocampal subicular dendrites

IntroductionAlzheimer's disease (AD) is linked to neuronal calcium dyshomeostasis, which is associated with network hyperexcitability. Decreased expression of the calcium-binding protein calbindin-D28K (CB) might be a susceptibility factor for AD. The subiculum is affected early in AD, for unknown reasons. MethodsIn AD, CB knock-out and control mice fluorescence Ca2+ imaging combined with patch clamp were used to characterize Ca2+ dynamics, resting Ca2+, and Ca2+-buffering capacity in subicular neurons. CB expression levels in wild-type and AD mice were also analyzed. ResultsThe subiculum and dentate gyrus of wild-type mice showed age-related decline in CB expression not observed in AD mice. Resting Ca2+ and Ca2+-buffering capacity was increased in aged AD mice subicular dendrites. Modeling suggests that AD calcium changes can be explained by alterations of Ca2+ extrusion pumps rather than by buffers. DiscussionOverall, abnormal Ca2+ homeostasis in AD has an age dependency that comprises multiple mechanisms, including compensatory processes.

Association between altered hippocampal oligodendrocyte number and neuronal circuit structures in schizophrenia: a postmortem analysis.

In schizophrenia, decreased hippocampal volume, reduced oligodendrocyte numbers in hippocampal cornu ammonis (CA) subregions and reduced neuron number in the dentate gyrus have been reported; reduced oligodendrocyte numbers were significantly related to cognitive deficits. The hippocampus is involved in cognitive functions and connected to the hypothalamus, anterior thalamus, and cingulate cortex, forming the Papez circuit, and to the mediodorsal thalamus. The relationship between the volume of these interconnected regions and oligodendrocyte and neuron numbers in schizophrenia is unknown. Therefore, we used stepwise logistic regression with subsequent multivariate stepwise linear regression and bivariate correlation to analyze oligodendrocyte and neuron numbers in the posterior hippocampal subregions CA1, CA2/3, CA4, dentate gyrus, and subiculum and volumes of the hippocampal CA region, cingulum, anterior and mediodorsal thalamus and hypothalamus in postmortem brains of 10 schizophrenia patients and 11 age- and gender-matched healthy controls. Stepwise logistic regression identified the following predictors for diagnosis, in order of inclusion: (1) oligodendrocyte number in CA4, (2) hypothalamus volume, (3) oligodendrocyte number in CA2/3, and (4) mediodorsal thalamus volume. Subsequent stepwise linear regression analyses identified the following predictors: (1) for oligodendrocyte number in CA4: (a) oligodendrocyte number in CA2/3, (b) diagnostic group, (c) hypothalamus volume, and (d) neurons in posterior subiculum; (2) for hypothalamus volume: (a) mediodorsal thalamus volume; (3) for oligodendrocyte number in CA2/3: oligodendrocyte number (a) in posterior CA4 and (b) in posterior subiculum; (4) for mediodorsal thalamus volume: volumes of (a) anterior thalamus and (b) hippocampal CA. In conclusion, we found a positive relationship between hippocampal oligodendrocyte number and the volume of the hypothalamus, a brain region connected to the hippocampus, which is important for cognition.

CA1-projecting subiculum neurons facilitate object-place learning.

Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to CA1. Here we show that the afferent circuitry of CA1-projecting subicular neurons is biased by inputs from CA1 inhibitory neurons as well as visual cortex, but lacks input from entorhinal cortex. Efferents of the CA1-projecting subiculum neurons also target perirhinal cortex, an area strongly implicated in object-place learning. We identify a critical role for CA1-projecting subicular neurons in object-location learning and memory, and show that this projection modulates place-specific activity of CA1 neurons as well as their responses to displaced objects. Together, these experiments reveal a novel pathway by which cortical inputs, particularly those from visual cortex, reach hippocampal output region CA1, and our findings implicate this circuitry in the formation of complex spatial representations and learning of object-place associations.

The Role of Free Oxygen Radicals in Lasting Hyperexcitability of Rat Subicular Neurons After Exposure to General Anesthesia During Brain Development.

A large number of preclinical studies have established that general anesthetics (GAs) may cause neurodevelopmental toxicity in rodents and nonhuman primates, which is followed by long-term cognitive deficits. The subiculum, the main output structure of hippocampal formation, is one of the brain regions most sensitive to exposure to GAs at the peak of synaptogenesis (i.e., postnatal day (PND) 7). We have previously shown that subicular neurons exposed to GAs produce excessive amounts of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), which is a known modulator of neuronal excitability. To further explore the association between GA-mediated increase in ROS levels and long-term functional changes within subicular neurons, we sought to investigate the effects of ROS on excitability of these neurons using patch-clamp electrophysiology in acute rat brain slices. We hypothesized that both acute application of H2O2 and an early exposure (at PND 7) to GA consisting of midazolam (9mg/kg), 70% nitrous oxide, and 0.75% isoflurane can affect excitability of subicular neurons and that superoxide dismutase and catalase mimetic, EUK-134, may reverse GA-mediated hyperexcitability in the subiculum. Our results using whole-cell recordings demonstrate that acute application of H2O2 has bidirectional effects on neuronal excitability: lower concentrations (0.001%, 0.3mM) cause an excitatory effect, whereas higher concentrations (0.01%, 3mM) inhibited neuronal firing. Furthermore, 0.3mM H2O2 increased the average action potential frequency of subicular neurons by almost twofold, as assessed using cell-attach configuration. Finally, we found that preemptive in vivo administration of EUK-134 reduced GA-induced long-lasting hyperexcitability of subicular neurons ex vivo when studied in neonatal and juvenile rats. This finding suggests that the increase in ROS after GA exposure may play an important role in regulating neuronal excitability, thus making it an attractive therapeutic target for GA-induced neurotoxicity in neonates.

Epileptiform activity reduced by lactate through HCA1 and GIRK channel activation in rat subicular neurons

Epileptiform activity reduced by lactate through HCA1 and GIRK channel activation in rat subicular neurons

Cholinergic modulation of the intrinsic properties of subicular neuron via direct suppression of HCN channel

Cholinergic modulation of the intrinsic properties of subicular neuron via direct suppression of HCN channel

Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy

SCN8A epileptic encephalopathy is a severe genetic epilepsy syndrome caused by de novo gain-of-function mutations of SCN8A encoding the voltage-gated sodium (Na) channel (VGSC) NaV1.6. Therapeutic management is difficult in many patients, leading to uncontrolled seizures and risk of sudden unexpected death in epilepsy (SUDEP). There is a need to develop novel anticonvulsants that can specifically target aberrant VGSC activity associated with SCN8A gain-of-function mutations. In this study, we investigate the effects of Prax330, a novel VGSC inhibitor, on the biophysical properties of wild-type (WT) NaV1.6 and the patient mutation p.Asn1768Asp (N1768D) in ND7/23 cells. The effects of Prax330 on persistent (INaP) and resurgent (INaR) Na currents and neuronal excitability in subiculum neurons from a knock-in mouse model of the Scn8a-N1768D mutation (Scn8aD/+) were also examined. In ND7/23 cells, Prax330 reduced INaP currents recorded from cells expressing Scn8a-N1768D and hyperpolarized steady-state inactivation curves. Recordings from brain slices demonstrated elevated INaP and INaR in subiculum neurons from Scn8aD/+ mutant mice and abnormally large action potential (AP) burst-firing events in a subset of neurons. Prax330 (1 μM) reduced both INaP and INaR and suppressed AP bursts, with a smaller effect on AP waveforms that had similar morphology to WT neurons. Prax330 (1 μM) also reduced synaptically-evoked APs in Scn8aD/+ subiculum neurons but not in WT neurons. Our results highlight the efficacy of targeting INaP and INaR and inactivation parameters in controlling subiculum excitability and suggest Prax330 as a promising novel therapy for SCN8A epileptic encephalopathy.

Chronic social defeat stress increases burst firing of nucleus accumbens-projecting ventral subicular neurons in stress-susceptible mice

The ventral subiculum (vSub) is the major output structure of the hippocampus and serves as a main limbic region in mediating the brain's response to stress. Previously, we reported that there are three subtypes of vSub neurons based on their firing patterns: regular-spiking (RS), weak-bursting (WB) and strong-bursting (SB) neurons and chronic social defeat stress (CSDS) increased SB neurons especially in the proximal vSub. Here, we found that neurons in the proximal vSub projected to the nucleus accumbens (NAc). CSDS significantly increased SB neurons but decreased RS neurons among the NAc-projecting vSub neuronal population. Interestingly, these changes were only apparent in mice susceptible to CSDS, but not in CSDS-resilient ones. Given that ventral hippocampal inputs to the NAc regulate susceptibility to CSDS, the bursting activity of NAc-projecting vSub neurons might be functionally relevant to behavioral susceptibility to CSDS.

Burst Firing and Spatial Coding in Subicular Principal Cells.

The subiculum is the major output structure of the hippocampal formation and is involved in learning and memory as well as in spatial navigation. Little is known about how neuronal diversity contributes to function in the subiculum. Previously, in vitro studies have identified distinct bursting patterns in the subiculum. Here, we asked how burst firing is related to spatial coding in vivo. Using juxtacellular recordings in freely moving male rats, we studied the bursting behavior of 102 subicular principal neurons and distinguished two populations: sparsely bursting (∼80%) and dominantly bursting neurons (∼20%). These bursting behaviors were not linked to anatomy: both cell types were found all along the proximodistal and radial axes of the subiculum and all identified cells were pyramidal neurons. However, the distinct burst firing patterns were related to functional differences: the activity of sparsely bursting cells showed a stronger spatial modulation than the activity of dominantly bursting neurons. In addition, all cells classified as boundary cells were sparsely bursting cells. In most sparsely bursting cells, bursts defined sharper firing fields and carried more spatial information than isolated spikes. We conclude that burst firing is functionally relevant to subicular spatially tuned neurons, possibly by serving as a mechanism to transmit spatial information to downstream structures.SIGNIFICANCE STATEMENT The subiculum is the major output structure of the hippocampal formation and is involved in spatial navigation. In vitro, subicular cells can be distinguished by their ability to initiate bursts as brief sequences of spikes fired at high frequencies. Little is known about the relationship between cellular diversity and spatial coding in the subiculum. We performed high-resolution juxtacellular recordings in freely moving rats and found that bursting behavior predicts functional differences between subicular neurons. Specifically, sparsely bursting cells have lower firing rates and carry more spatial information than dominantly bursting cells. Additionally, bursts fired by sparsely bursting cells encoded spatial information better than isolated spikes, indicating that bursts act as a unit of information dedicated to spatial coding.

Chronic social defeat stress-induced enhancement of T-type calcium channels increases burst-firing neurons in the ventral subiculum

The ventral subiculum (vSub), a representative output structure of the hippocampus, serves as a main limbic region in mediating the brain's response to stress. There are three subtypes of subicular pyramidal neurons based on their firing patterns: regular-spiking (RS), weak-bursting (WB) and strong-bursting (SB) neurons, located differently along proximal–distal axis. Here, we found that chronic social defeat stress (CSDS) in mice increased the population of SB neurons but decreased RS neurons in the proximal vSub. Specific blockers of T-type calcium channels inhibited the burst firings with a concomitant reduction of afterdepolarization, suggesting that T-type calcium channels underlie the burst-spiking activity. Consistently, CSDS increased both T-type calcium currents and expression of Cav3.1 proteins, a subtype of T-type calcium channels, in the proximal vSub. Therefore, we conclude that CSDS-induced enhancement of Cav3.1 expression increased bursting neuronal population in the vSub, which may contribute to stress-related behaviors.

New Hippocampal Circuit Organization Revealed by Viral‐genetic Tracing and Functional Circuit Mapping

The hippocampal formation plays essential roles in learning and memory, and spatial navigation. Although the general anatomy and circuit organization of hippocampal CA1 has been well‐studied, most of our understanding of hippocampal circuits comes from the conventional anatomical tracing studies which lack cell‐type specificity and quantitative measurements of connectional strengths. New advances in virology and molecular genetics complement traditional approaches and are powerful tools for mapping cell‐type‐specific circuit connectivity and function. Using monosynaptic rabies tracing, we recently discovered a non‐canonical but significant set of back‐projections comprised of both excitatory and inhibitory elements from the subiculum to CA1 in the mouse. This discovery suggests previously unconsidered functional roles for direct subicular modulation of hippocampal CA1 circuit activity. In this talk, I will first report our quantitative analysis of canonical‐ and non‐canonical inputs to excitatory neurons in dorsal hippocampal CA1. We find that comparable strength of subiculum complex and entorhinal cortex (EC) inputs to CA1, significant inputs from presubiculum and parasubiculum to CA1, and a threefold stronger input to proximal versus distal CA1 from CA3. Non‐canonical subicular complex inputs exhibit opposing topographic connectivity gradients whereby the subiculum‐CA1 input strength systematically increases but the presubiculum‐CA1 input strength decreases along the proximal‐distal axis. These results reveal a novel anatomical framework by which to determine the circuit bases for CA1 physiological representations. Further, to test the hypothesis that CA1‐projecting subiculum neurons integrate strong CA1 and local subicular inputs to exert direct feedback regulation of CA1 circuit activity, we map and compare global circuit input and output connections of CA1‐projecting and other excitatory subicular neurons using retrograde monosynaptic rabies tracing and anterograde directed herpes simplex virus (H129 strain) in intact brains, respectively. In conjunction with behavior analysis and genetically targeted neuronal activation and inactivation, in vivo GCaMP6‐based calcium imaging of CA1 neurons in freely moving animals is used to resolve how CA1‐projecting subicular neurons modulate CA1 place cell activity and how they contribute to location dependent learning and memory. Together, these studies provide new insights into this subicular‐CA1 pathway, and advance our understanding of how the subiculum interacts with CA1 to regulate hippocampal circuit activity and learning and memory behaviors.Support or Funding InformationThis research is supported by the National Institutes of Health grant (R01NS078434).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Teneurin-3 controls topographic circuit assembly in the hippocampus.

Brain functions rely on specific patterns of connectivity. Teneurins are evolutionarily conserved transmembrane proteins that instruct synaptic partner matching in Drosophila and are required for vertebrate visual system development. The roles of vertebrate teneurins in connectivity beyond the visual system remain largely unknown and their mechanisms of action have not been demonstrated. Here we show that mouse teneurin-3 is expressed in multiple topographically interconnected areas of the hippocampal region, including proximal CA1, distal subiculum, and medial entorhinal cortex. Viral-genetic analyses reveal that teneurin-3 is required in both CA1 and subicular neurons for the precise targeting of proximal CA1 axons to distal subiculum. Furthermore, teneurin-3 promotes homophilic adhesion in vitro in a splicing isoform-dependent manner. These findings demonstrate striking genetic heterogeneity across multiple hippocampal areas and suggest that teneurin-3 may orchestrate the assembly of a complex distributed circuit in the mammalian brain via matching expression and homophilic attraction.

Differential Rate Coding of Visual Context in the Subiculum and Hippocampus

Discharge rates of place cells in the hippocampus are modulated by changes in the sensory environment. Such rate remapping may underlie the neural code responsible for remembering different events that take place in the same location, but it is unknown if rate remapping is a code unique to the hippocampus. Recordings from neurons in the rat subiculum and CA1 during a visual contextual me mory task showed that contextual rate remapping occurred more strongly in the subiculum than the CA1 during recognition of a familiar visual context. However, increases in contextual ambiguity led to a decrease in both performance and context-specific firing in the CA1; by contrast, no such ambiguity-related neural correlate was found in the subiculum. Our findings suggest that rate remapping occurs globally in the brain, but recognizing an altered environment may be a unique function of the hippocampus.

Collateral Projections Innervate the Mammillary Bodies and Retrosplenial Cortex: A New Category of Hippocampal Cells.

To understand the hippocampus, it is necessary to understand the subiculum. Unlike other hippocampal subfields, the subiculum projects to almost all distal hippocampal targets, highlighting its critical importance for external networks. The present studies, in male rats and mice, reveal a new category of dorsal subiculum neurons that innervate both the mammillary bodies (MBs) and the retrosplenial cortex (RSP). These bifurcating neurons comprise almost half of the hippocampal cells that project to RSP. The termination of these numerous collateral projections was visualized within the medial mammillary nucleus and the granular RSP (area 29). These collateral projections included subiculum efferents that cross to the contralateral MBs. Within the granular RSP, the collateral projections form a particularly dense plexus in deep Layer II and Layer III. This retrosplenial termination site colocalized with markers for VGluT2 and neurotensin. While efferents from the hippocampal CA fields standardly collateralize, subiculum projections often have only one target site. Consequently, the many collateral projections involving the RSP and the MBs present a relatively unusual pattern for the subiculum, which presumably relates to how both targets have complementary roles in spatial processing. Furthermore, along with the anterior thalamic nuclei, the MBs and RSP are key members of a memory circuit, which is usually described as both starting and finishing in the hippocampus. The present findings reveal how the hippocampus simultaneously engages different parts of this circuit, so forcing an important revision of this network.

Pro-excitatory alterations in sodium channel activity facilitate subiculum neuron hyperexcitability in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is a common form of adult epilepsy involving the limbic structures of the temporal lobe. Subiculum neurons act to provide a major output from the hippocampus and consist of a large population of endogenously bursting excitatory neurons. In TLE, subiculum neurons are largely spared, become hyperexcitable and show spontaneous epileptiform activity. The basis for this hyperexcitability is unclear, but is likely to involve alterations in the expression levels and function of various ion channels. In this study, we sought to determine the importance of sodium channel currents in facilitating neuronal hyperexcitability of subiculum neurons in the continuous hippocampal stimulation (CHS) rat model of TLE. Subiculum neurons from TLE rats were hyperexcitable, firing a higher frequency of action potentials after somatic current injection and action potential (AP) bursts after synaptic stimulation. Voltage clamp recordings revealed increases in resurgent (INaR) and persistent (INaP) sodium channel currents and pro-excitatory shifts in sodium channel activation and inactivation parameters that would facilitate increases in AP generation. Attenuation of INaR and INaP currents with 4,9-anhydro-tetrodotoxin (4,9-ah TTX; 100nM), a toxin with increased potency against Nav1.6 channels, suppressed neuronal firing frequency and inhibited AP bursting induced by synaptic stimulation in TLE neurons. These findings support an important role of sodium channels, particularly Nav1.6, in facilitating subiculum neuron hyperexcitability in TLE and provide further support for the importance of INaR and INaP currents in establishing epileptiform activity of subiculum neurons.

Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit

The entorhinal cortex (EC) is affected early in Alzheimer's disease, an illness defined by a co-occurrence of tau and amyloid-related pathologies. How the co-occurrence of these pathologies in the EC affects the hippocampal circuit remains unknown. Here we address this question by performing electrophysiological analyses of the EC circuit in mice that express mutant human amyloid precursor protein (hAPP) or tau (hTau), or both in the EC. We show that the alterations in the hippocampal circuit are divergent, with hAPP increasing but hTau decreasing neuronal/circuit excitability. Most importantly, mice co-expressing hAPP and hTau show that hTau has a dominant effect, dampening the excitatory effects of hAPP. Additionally, compensatory synaptic downscaling, in response to increased excitability in EC was observed in subicular neurons of hAPP mice. Based on simulations, we propose that EC interneuron pruning can account for both EC hyperexcitability and subicular synaptic downscaling found in mice expressing hAPP.

The role of T-type calcium channels in the subiculum: to burst or not to burst?

Pharmacological, molecular and genetic data indicate a prominent role of low-voltage-activated T-type calcium channels (T-channels) in the firing activity of both pyramidal and inhibitory interneurons in the subiculum. Pharmacological inhibition of T-channels switched burst firing with lower depolarizing stimuli to regular spiking, and fully abolished hyperpolarization-induced burst firing. Our molecular studies showed that CaV 3.1 is the most abundantly expressed isoform of T-channels in the rat subiculum. Consistent with this finding, both regular-spiking and burst firing patterns were profoundly depressed in the mouse with global deletion of CaV 3.1 isoform of T-channels. Selective inhibition of T-channels and global deletion of CaV 3.1 channels completely suppressed development of long-term potentiation (LTP) in the CA1-subiculum, but not in the CA3-CA1 pathway. Several studies suggest that voltage-gated calcium currents are involved in generating high frequency burst firing in the subiculum, but the exact nature of these currents remains unknown. Here, we used selective pharmacology, molecular and genetic approaches to implicate Cav3.1-containing T-channels in subicular burst firing, in contrast to several previous reports discounting T-channels as major contributors to subicular neuron physiology. Furthermore, pharmacological antagonism of T-channels, as well as global deletion of CaV3.1 isoform, completely suppressed development of long-term potentiation (LTP) in the CA1-subiculum, but not in the CA3-CA1 pathway. Our results indicate that excitability and synaptic plasticity of subicular neurons relies heavily on T-channels. Hence, T-channels may be a promising new drug target for different cognitive deficits.

Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice.

Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.