Vivien Chevaleyre

Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes

Specification of cell identity during development depends on exposure of cells to sequences of extrinsic cues delivered at precise times and concentrations. Identification of combinations of patterning molecules that control cell fate is essential for the effective use of human pluripotent stem cells (hPSCs) for basic and translational studies. Here we describe a scalable, automated approach to systematically test the combinatorial actions of small molecules for the targeted differentiation of hPSCs. Applied to the generation of neuronal subtypes, this analysis revealed an unappreciated role for canonical Wnt signaling in specifying motor neuron diversity from hPSCs and allowed us to define rapid (14 days), efficient procedures to generate spinal and cranial motor neurons as well as spinal interneurons and sensory neurons. Our systematic approach to improving hPSC-targeted differentiation should facilitate disease modeling studies and drug screening assays.

Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome

Several neuropsychiatric disorders are associated with cognitive and social dysfunction. Postmortem studies of patients with schizophrenia have revealed specific changes in area CA2, a long-overlooked region of the hippocampus recently found to be critical for social memory formation. To examine how area CA2 is altered in psychiatric illness, we used the Df(16)A(+/-) mouse model of the 22q11.2 microdeletion, a genetic risk factor for developing several neuropsychiatric disorders, including schizophrenia. We report several age-dependent CA2 alterations: a decrease in the density of parvalbumin-expressing interneurons, a reduction in the amount of feedforward inhibition, and a change in CA2 pyramidal-neuron intrinsic properties. Furthermore, we found that area CA2 is less plastic in Df(16)A(+/-) mice, making it nearly impossible to evoke action potential firing in CA2 pyramidal neurons. Finally, we show that Df(16)A(+/-) mice display impaired social cognition, providing a potential mechanism and a neural substrate for this impairment in psychiatric disorders.

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.

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.

Inhibitory Plasticity Permits the Recruitment of CA2 Pyramidal Neurons by CA3

Abstract Area CA2 is emerging as an important region for hippocampal memory formation. However, how CA2 pyramidal neurons (PNs) are engaged by intrahippocampal inputs remains unclear. Excitatory transmission between CA3 and CA2 is strongly inhibited and is not plastic. We show in mice that different patterns of activity can in fact increase the excitatory drive between CA3 and CA2. We provide evidence that this effect is mediated by a long-term depression at inhibitory synapses (iLTD), as it is evoked by the same protocols and shares the same pharmacology. In addition, we show that the net excitatory drive of distal inputs is also increased after iLTD induction. The disinhibitory increase in excitatory drive is sufficient to allow CA3 inputs to evoke action potential firing in CA2 PNs. Thus, these data reveal that the output of CA2 PNs can be gated by the unique activity-dependent plasticity of inhibitory neurons in area CA2.

Chronic Loss of CA2 Transmission Leads to Hippocampal Hyperexcitability

Hippocampal CA2 pyramidal cells project into both the neighboring CA1 and CA3 subfields, leaving them well positioned to influence network physiology and information processing for memory and space. While recent work has suggested unique roles for CA2, including encoding position during immobility and generating ripple oscillations, an interventional examination of the integrative functions of these connections has yet to be reported. Here we demonstrate that CA2 recruits feedforward inhibition in CA3 and that chronic genetically engineered shutdown of CA2-pyramidal-cell synaptic transmission consequently results in increased excitability of the recurrent CA3 network. In behaving mice, this led to spatially triggered episodes of network-wide hyperexcitability during exploration accompanied by the emergence of high-frequency discharges during rest. These findings reveal CA2 as a regulator of network processing in hippocampus and suggest that CA2-mediated inhibition in CA3 plays a key role in establishing the dynamic excitatory and inhibitory balance required for proper network function.

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

HighlightsDistal input high frequency stimulation triggers inhibitory transmission LTD in CA2.Distal input high frequency stimulation can also depress proximal inhibition in CA2.LTD results in a dis‐inhibitory increase in proximal and distal excitatory potentials.The inhibitory LTD and dis‐inhibition require delta‐opioid receptor activation.The dis‐inhibition allows proximal inputs to evoke AP firing in CA2 pyramidal neurons. Abstract 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.

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.

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.

Heterogeneity in Kv2 channel expression shapes action potential characteristics and firing patterns in CA1 versus CA2 hippocampal pyramidal neurons

Abstract The CA1 region of the hippocampus plays a critical role in spatial and contextual memory, and has well-established circuitry, function and plasticity. In contrast, the properties of the flanking CA2 pyramidal neurons (PNs), important for social memory, and lacking CA1-like plasticity, remain relatively understudied. In particular, little is known regarding the expression of voltage-gated K+ (Kv) channels and the contribution of these channels to the distinct properties of intrinsic excitability, action potential (AP) waveform, firing patterns and neurotransmission between CA1 and CA2 PNs. In the present study, we used multiplex fluorescence immunolabeling of mouse brain sections, and whole-cell recordings in acute mouse brain slices, to define the role of heterogeneous expression of Kv2 family Kv channels in CA1 versus CA2 pyramidal cell excitability. Our results show that the somatodendritic delayed rectifier Kv channel subunits Kv2.1, Kv2.2, and their auxiliary subunit AMIGO-1 have region-specific differences in expression in PNs, with the highest expression levels in CA1, a sharp decrease at the CA1-CA2 boundary, and significantly reduced levels in CA2 neurons. PNs in CA1 exhibit a robust contribution of Guangxitoxin-1E-sensitive Kv2-based delayed rectifier current to AP shape and after-hyperpolarization potential (AHP) relative to that seen in CA2 PNs. Our results indicate that robust Kv2 channel expression confers a distinct pattern of intrinsic excitability to CA1 PNs, potentially contributing to their different roles in hippocampal network function.