A hypothalamic novelty signal modulates hippocampal memory.

The ability to recognize information that is incongruous with previous experience is critical for survival. Novelty signals have therefore evolved in the mammalian brain to enhance attention, perception and memory1,2. Although the importance of regions such as the ventral tegmental area3,4 and locus coeruleus5 in broadly signalling novelty is well-established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information on the type of stimuli that drive them. Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain is unknown. Here we identify the supramammillary nucleus (SuM) as a novelty hub in the hypothalamus6. The SuM region is unique in that it not only responds broadly to novel stimuli, but also segregates and selectively routes different types of information to discrete cortical targets-the dentate gyrus and CA2 fields of the hippocampus-for the modulation of mnemonic processing. Using a new transgenic mouse line, SuM-Cre, we found that SuM neurons that project to the dentate gyrus are activated by contextual novelty, whereas the SuM-CA2 circuit is preferentially activated by novel social encounters. Circuit-based manipulation showed that divergent novelty channelling in these projections modifies hippocampal contextual or social memory. This content-specific routing of novelty signals represents a previously unknown mechanism that enables the hypothalamus to flexibly modulate select components of cognition.

Environmental enrichment and social isolation modulate inhibitory transmission and plasticity in hippocampal area CA2.

Environmental factors are well-accepted to play a complex and interdependent role with genetic factors in learning and memory. The goal of this study was to examine how environmental conditions altered synaptic plasticity in hippocampal area CA2. To do this, we housed adult mice for 3 weeks in an enriched environment (EE) consisting of a larger cage with running wheel, and regularly changed toys, tunnels and treats. We then performed whole-cell or extracellular field recordings in hippocampal area CA2 and compared the synaptic plasticity from EE-housed mice with slices from littermate controls housed in standard environment (SE). We found that the inhibitory transmission recruited by CA3 input stimulation in CA2 was significantly less plastic in EE conditions as compared to SE following an electrical tetanus. We demonstrate that delta-opioid receptor (DOR) mediated plasticity is reduced in EE conditions by direct application of DOR agonist. We show that in EE conditions the overall levels of GABA transmission is reduced in CA2 cells by analyzing inhibition of ErbB4 receptor, spontaneous inhibitory currents and paired-pulse ratio. Furthermore, we report that the effect of EE of synaptic plasticity can be rapidly reversed by social isolation. These results demonstrate how the neurons in hippocampal area CA2 are sensitive to environment and may lead to promising therapeutic targets.

Activation of the PI3K/AKT/mTOR Pathway in Cajal-Retzius Cells Leads to Their Survival and Increases Susceptibility to Kainate-Induced Seizures.

Cajal-Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases. To decipher the molecular mechanisms involved in CR death, we investigated the contribution of the PI3K/AKT/mTOR pathway as it plays a critical role in cell survival. We first showed that this pathway is less active in CRs after birth before massive cell death. We also explored the spatio-temporal activation of both AKT and mTOR pathways and reveal area-specific differences along both the rostro-caudal and medio-lateral axes. Next, using genetic approaches to maintain an active pathway in CRs, we found that the removal of either PTEN or TSC1, two negative regulators of the pathway, lead to differential CR survivals, with a stronger effect in the Pten model. Persistent cells in this latter mutant are still active. They express more Reelin and their persistence is associated with an increase in the duration of kainate-induced seizures in females. Altogether, we show that the decrease in PI3K/AKT/mTOR activity in CRs primes these cells to death by possibly repressing a survival pathway, with the mTORC1 branch contributing less to the phenotype.

Hippocampal area CA2: properties and contribution to hippocampal function.

This review focuses on area CA2 of the hippocampus, as recent results have revealed the unique properties and surprising role of this region in encoding social, temporal and contextual aspects of memory. Originally identified and described by Lorente de No, in 1934, this region of the hippocampus has unique intra-and extra-hippocampal connectivity, sending and receiving input to septal and hypothalamic regions. Recent in vivo studies have indicated that CA2 pyramidal neurons encode spatial information during immobility and play an important role in the generation of sharp-wave ripples. Furthermore, CA2 neurons act to control overall excitability in the hippocampal network and have been found to be consistently altered in psychiatric diseases, indicating that normal function of this region is necessary for normal cognition. With its unique role, area CA2 has a unique molecular profile, interneuron density and composition. Furthermore, this region has an unusual manifestation of synaptic plasticity that does not occur post-synaptically at pyramidal neuron dendrities but through the local network of inhibitory neurons. While much progress has recently been made in understanding the large contribution of area CA2 to social memory formation, much still needs to be learned.

Bi-directional interplay between proximal and distal inputs to CA2 pyramidal neurons.

Hippocampal area CA2 is emerging as a critical region for memory formation. Excitatory Scaffer collateral (SC) inputs from CA3 do not express activity-dependent plasticity at SC-CA2 synapses, and are governed by a large feed-forward inhibition that prevents them from engaging CA2 pyramidal neurons. However, long-term depression at inhibitory synapses evoked by stimulation of SC inputs highly increases the excitatory/inhibitory balance coming from CA3 and allows the recruitment of CA2 pyramidal neurons. In contrast, distal excitatory inputs in stratum lacunosum moleculare (SLM) can drive action potential firing in CA2 pyramidal neurons and also express a long-term potentiation. However, it is unknown whether stimulation of distal inputs can also evoke plasticity at inhibitory synapses and if so, whether this plasticity can control the strength of excitatory inputs. Here we show that stimulation in SLM evokes a long-term depression at inhibitory synapses. This plasticity strongly increases the excitatory drive of both proximal and distal inputs and allows CA3 to recruit CA2 pyramidal neurons. These data reveal a bi-directional interplay between proximal and distal inputs to CA2 pyramidal neurons that is likely to play an important role in information transfer through the hippocampus.

Delta-opioid receptors mediate unique plasticity onto parvalbumin-expressing interneurons in area CA2 of the hippocampus.

Inhibition is critical for controlling information transfer in the brain. However, the understanding of the plasticity and particular function of different interneuron subtypes is just emerging. Using acute hippocampal slices prepared from adult mice, we report that in area CA2 of the hippocampus, a powerful inhibitory transmission is acting as a gate to prevent CA3 inputs from driving CA2 neurons. Furthermore, this inhibition is highly plastic, and undergoes a long-term depression following high-frequency 10 Hz or theta-burst induction protocols. We describe a novel form of long-term depression at parvalbumin-expressing (PV+) interneuron synapses that is dependent on delta-opioid receptor (DOR) activation. Additionally, PV+ interneuron transmission is persistently depressed by DOR activation in area CA2 but only transiently depressed in area CA1. These results provide evidence for a differential temporal modulation of PV+ synapses between two adjacent cortical circuits, and highlight a new function of PV+ cells in controlling information transfer.

Adolescent cannabinoid exposure rescues phencyclidine-induced social deficits through modulation of CA2 transmission.

Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use cannabis tend to show less severe deficits in social behaviors, such as the misinterpretation of social cues and the inability to interact with others. However, the biological underpinnings of this epidemiological interaction remain unclear. Here, we used the NMDA receptor blocker phencyclidine (PCP) to induce psychotic-like states and to study the impact of adolescent cannabinoid exposure on social behavior deficits and synaptic transmission changes in hippocampal area CA2, a region known to be active during social interactions. In particular, adolescent mice underwent 7 days of subchronic treatment with the synthetic cannabinoid, WIN 55, 212-2 (WIN) followed by one injection of PCP. Using behavioral, biochemical, and electrophysiological approaches, we showed that PCP persistently reduced sociability, decreased GAD67 expression in the hippocampus, and induced GABAergic deficits in proximal inputs from CA3 and distal inputs from the entorhinal cortex (EC) to CA2. Notably, WIN exposure during adolescence specifically restores adult sociability deficits, the expression changes in GAD67, and the GABAergic impairments in the EC-CA2 circuit, but not in the CA3-CA2 circuit. Using a chemogenetic approach to target EC-CA2 projections, we demonstrated the involvement of this specific circuit on sociability deficits. Indeed, enhancing EC-CA2 transmission was sufficient to induce sociability deficits in vehicle-treated mice, but not in animals treated with WIN during adolescence, suggesting a mechanism by which adolescent cannabinoid exposure rescues sociability deficits caused by enhanced EC-CA2 activity in adult mice.

Synaptic integration by different dendritic compartments of hippocampal CA1 and CA2 pyramidal neurons.

Pyramidal neurons have a complex dendritic arbor containing tens of thousands of synapses. In order for the somatic/axonal membrane potential to reach action potential threshold, concurrent activation of multiple excitatory synapses is required. Frequently, instead of a simple algebraic summation of synaptic potentials in the soma, different dendritic compartments contribute to the integration of multiple inputs, thus endowing the neuron with a powerful computational ability. Most pyramidal neurons share common functional properties. However, different and sometimes contrasting dendritic integration rules are also observed. In this review, we focus on the dendritic integration of two neighboring pyramidal neurons in the hippocampus: the well-characterized CA1 and the much less understood CA2. The available data reveal that the dendritic integration of these neurons is markedly different even though they are targeted by common inputs at similar locations along their dendrites. This contrasting dendritic integration results in different routing of information flow and generates different corticohippocampal loops.

Hippocampal area CA2: interneuron disfunction during pathological states.

Hippocampal area CA2 plays a critical role in social recognition memory and has unique cellular and molecular properties that distinguish it from areas CA1 and CA3. In addition to having a particularly high density of interneurons, the inhibitory transmission in this region displays two distinct forms of long-term synaptic plasticity. Early studies on human hippocampal tissue have reported unique alteration in area CA2 with several pathologies and psychiatric disorders. In this review, we present recent studies revealing changes in inhibitory transmission and plasticity of area CA2 in mouse models of multiple sclerosis, autism spectrum disorder, Alzheimer's disease, schizophrenia and the 22q11.2 deletion syndrome and propose how these changes could underly deficits in social cognition observed during these pathologies.

TRIP8b regulates HCN1 channel trafficking and gating through two distinct C-terminal interaction sites.

Hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the brain associate with their auxiliary subunit TRIP8b (also known as PEX5R), a cytoplasmic protein expressed as a family of alternatively spliced isoforms. Recent in vitro and in vivo studies have shown that association of TRIP8b with HCN subunits both inhibits channel opening and alters channel membrane trafficking, with some splice variants increasing and others decreasing channel surface expression. Here, we address the structural bases of the regulatory interactions between mouse TRIP8b and HCN1. We find that HCN1 and TRIP8b interact at two distinct sites: an upstream site where the C-linker/cyclic nucleotide-binding domain of HCN1 interacts with an 80 aa domain in the conserved central core of TRIP8b; and a downstream site where the C-terminal SNL (Ser-Asn-Leu) tripeptide of the channel interacts with the tetratricopeptide repeat domain of TRIP8b. These two interaction sites play distinct functional roles in the effects of TRIP8b on HCN1 trafficking and gating. Binding at the upstream site is both necessary and sufficient for TRIP8b to inhibit channel opening. It is also sufficient to mediate the trafficking effects of those TRIP8b isoforms that downregulate channel surface expression, in combination with the trafficking motifs present in the N-terminal region of TRIP8b. In contrast, binding at the downstream interaction site serves to stabilize the C-terminal domain of TRIP8b, allowing for optimal interaction between HCN1 and TRIP8b as well as for proper assembly of the molecular complexes that mediate the effects of TRIP8b on HCN1 channel trafficking.

Spider toxins activate the capsaicin receptor to produce inflammatory pain.

Bites and stings from venomous creatures can produce pain and inflammation as part of their defensive strategy to ward off predators or competitors. Molecules accounting for lethal effects of venoms have been extensively characterized, but less is known about the mechanisms by which they produce pain. Venoms from spiders, snakes, cone snails or scorpions contain a pharmacopoeia of peptide toxins that block receptor or channel activation as a means of producing shock, paralysis or death. We examined whether these venoms also contain toxins that activate (rather than inhibit) excitatory channels on somatosensory neurons to produce a noxious sensation in mammals. Here we show that venom from a tarantula that is native to the West Indies contains three inhibitor cysteine knot (ICK) peptides that target the capsaicin receptor (TRPV1), an excitatory channel expressed by sensory neurons of the pain pathway. In contrast with the predominant role of ICK toxins as channel inhibitors, these previously unknown 'vanillotoxins' function as TRPV1 agonists, providing new tools for understanding mechanisms of TRP channel gating. Some vanillotoxins also inhibit voltage-gated potassium channels, supporting potential similarities between TRP and voltage-gated channel structures. TRP channels can now be included among the targets of peptide toxins, showing that animals, like plants (for example, chilli peppers), avert predators by activating TRP channels on sensory nerve fibres to elicit pain and inflammation.

Sequential inhibitory plasticities in hippocampal area CA2 and social memory formation.

Area CA2 is a critical region for diverse hippocampal functions including social recognition memory. This region has unique properties and connectivity. Notably, intra-hippocampal excitatory inputs to CA2 lack canonical long-term plasticity, but inhibitory transmission expresses a long-term depression mediated by Delta-opioid receptors (DOR-iLTDs). Evidence indicates that DOR-iLTDs are insufficient to underlie social coding. Here, we report a novel inhibitory plasticity mediated by cannabinoid type 1 receptor activation (CB1R-iLTD). Surprisingly, CB1R-iLTD requires previous induction of DOR-iLTDs, indicating a permissive role for DOR plasticity. Blockade of CB1Rs in CA2 completely prevents social memory formation. Furthermore, the sequentiality of DOR- and CB1R-mediated plasticity occurs in vivo during successive social interactions. Finally, CB1R-iLTD is altered in a mouse model of schizophrenia with impaired social cognition but is rescued by a manipulation that also rescues social memory. Altogether, our data reveal a unique interplay between two inhibitory plasticities and a novel mechanism for social memory formation.

Altered inhibitory function in hippocampal CA2 contributes in social memory deficits in Alzheimer's mouse model.

Parvalbumin (PV)-expressing interneurons which are often associated with the specific extracellular matrix perineuronal net (PNN) play a critical role in the alteration of brain activity and memory performance in Alzheimer's disease (AD). The integrity of these neurons is crucial for normal functioning of the hippocampal subfield CA2, and hence, social memory formation. Here, we find that social memory deficits of mouse models of AD are associated with decreased presence of PNN around PV cells and long-term synaptic plasticity in area CA2. Furthermore, single local injection of the growth factor neuregulin-1 (NRG1) is sufficient to restore both PV/PNN levels and social memory performance of these mice. Thus, the PV/PNN disruption in area CA2 could play a causal role in social memory deficits of AD mice, and activating PV cell pro-maturation pathways may be sufficient to restore social memory.

Local circuit allowing hypothalamic control of hippocampal area CA2 activity and consequences for CA1.

The hippocampus is critical for memory formation. The hypothalamic supramammillary nucleus (SuM) sends long-range projections to hippocampal area CA2. While the SuM-CA2 connection is critical for social memory, how this input acts on the local circuit is unknown. Using transgenic mice, we found that SuM axon stimulation elicited mixed excitatory and inhibitory responses in area CA2 pyramidal neurons (PNs). Parvalbumin-expressing basket cells were largely responsible for the feedforward inhibitory drive of SuM over area CA2. Inhibition recruited by the SuM input onto CA2 PNs increased the precision of action potential firing both in conditions of low and high cholinergic tone. Furthermore, SuM stimulation in area CA2 modulated CA1 activity, indicating that synchronized CA2 output drives a pulsed inhibition in area CA1. Hence, the network revealed here lays basis for understanding how SuM activity directly acts on the local hippocampal circuit to allow social memory encoding.

Increased seizure severity and seizure-related death in mice lacking HCN1 channels.

Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior.

The mechanisms shaping CA2 pyramidal neuron action potential bursting induced by muscarinic acetylcholine receptor activation.

Recent studies have revealed that hippocampal area CA2 plays an important role in hippocampal network function. Disruption of this region has been implicated in neuropsychiatric disorders. It is well appreciated that cholinergic input to the hippocampus plays an important role in learning and memory. While the effect of elevated cholinergic tone has been well studied in areas CA1 and CA3, it remains unclear how changes in cholinergic tone impact synaptic transmission and the intrinsic properties of neurons in area CA2. In this study, we applied the cholinergic agonist carbachol and performed on-cell, whole-cell, and extracellular recordings in area CA2. We observed that under conditions of high cholinergic tone, CA2 pyramidal neurons depolarized and rhythmically fired bursts of action potentials. This depolarization depended on the activation of M1 and M3 cholinergic receptors. Furthermore, we examined how the intrinsic properties and action-potential firing were altered in CA2 pyramidal neurons treated with 10 µM carbachol. While this intrinsic burst firing persisted in the absence of synaptic transmission, bursts were shaped by synaptic inputs in the intact network. We found that both excitatory and inhibitory synaptic transmission were reduced upon carbachol treatment. Finally, we examined the contribution of different channels to the cholinergic-induced changes in neuronal properties. We found that a conductance from Kv7 channels partially contributed to carbachol-induced changes in resting membrane potential and membrane resistance. We also found that D-type potassium currents contributed to controlling several properties of the bursts, including firing rate and burst kinetics. Furthermore, we determined that T-type calcium channels and small conductance calcium-activated potassium channels play a role in regulating bursting activity.

Maturation of PNN and ErbB4 Signaling in Area CA2 during Adolescence Underlies the Emergence of PV Interneuron Plasticity and Social Memory.

Adolescence is a vulnerable period characterized by major cognitive changes. The mechanisms underlying the emergence of new cognitive functions are poorly understood. We find that a long-term depression of inhibitory transmission (iLTD) from parvalbumin-expressing (PV+) interneurons in the hippocampal area Cornu Ammonis 2 (CA2) is absent in young mice but emerges at the end of adolescence. We demonstrate that the maturation of both the perineuronal net (PNN) and signaling through ErbB4 is required for this plasticity. Furthermore, we demonstrate that social recognition memory displays the same age dependence as iLTD and is impaired by targeted degradation of the PNN or iLTD blockade in area CA2. Our data reveal an unusual developmental rule for plasticity at the PV+ interneuron transmission in area CA2 and indicate that this plasticity is involved in the emergence of higher cognitive function, such as social memory formation, in late adolescence.

Routing Hippocampal Information Flow through Parvalbumin Interneuron Plasticity in Area CA2.

The hippocampus is critical for the formation of episodic memory. It is, therefore, important to understand intra-hippocampal circuitry, especially in the often overlooked area CA2. Using specific transgenic mouse lines combined with opto- and chemogenetics, we show that local plasticity of parvalbumin-expressing interneurons in area CA2 allows CA3 input to recruit CA2 pyramidal neurons (PNs), thereby increasing the excitatory drive between CA3 and CA1. CA2 PNs provide both stronger excitation and larger feed-forward inhibition onto deep, compared with superficial, CA1 PNs. This feed-forward inhibition, largely mediated by parvalbumin-expressing interneurons, normalizes the excitatory drive onto deep and superficial CA1 PNs. Finally, we identify a target of CA2 in area CA1, i.e., CA1 PNs, whose soma are located in stratum radiatum. These data provide insight into local hippocampal circuitry and reveal how localized plasticity can potentially control information flow in the larger hippocampal network.

Memory circuits: CA2.

The hippocampus is a central region in the coding of spatial, temporal and episodic memory. Recent discoveries have revealed surprising and complex roles of the small area CA2 in hippocampal function. Lesion studies have revealed that this region is required for social memory formation. Area CA2 is targeted by extra-hippocampal paraventricular inputs that release vasopressin and can act to enhance social memory performance. In vivo recordings have revealed nonconventional activity by neurons in this region that act to both initiate hippocampal sharp-wave ripple events as well as encode spatial information during immobility. Silencing of CA2 pyramidal neurons has revealed that this area also acts to control hippocampal network excitability during encoding, and this balance of excitation and inhibition is disrupted in disease. This review summarizes recent findings and attempts to integrate these results into pre-existing models.