Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory

Leroy, Félix; Brann, David H.; Meira, Torcato; Siegelbaum, Steven A.

doi:10.1016/j.neuron.2017.07.036

Cited by 78 publications

(89 citation statements)

References 60 publications

(115 reference statements)

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“…Our results contradict previous studies that report no IEG induction in the CA2 region of the hippocampus upon social stimuli Tanimizu et al, 2017), while supports findings from Kim et al that report CA2 activation upon social interaction (Kim et al, 2015). The hippocampus is critically integrated into the rodent circuitry involved in social behaviours (Kim et al, 2015;Ko, 2017;Kogan et al, 2000;Raam et al, 2017;, but specifically, the CA2 subfield is important for the formation of social memory Hitti and Siegelbaum, 2014;Leroy et al, 2017;Lin et al, 2017;Smith et al, 2016;Stevenson and Caldwell, 2014). Therefore, it is no surprise that we observe neuronal activation in the CA2 region upon social stimuli, a prerequisite to social memory formation (Felix-Ortiz and Tye, 2014;Hitti and Siegelbaum, 2014).…”

Section: Discussionsupporting

confidence: 66%

Impaired social behaviour and molecular mediators of associated neural circuits during chronicToxoplasma gondiiinfection in female mice

Tyebji

Seizova

Garnham

et al. 2018

Preprint

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Toxoplasma gondii (T. gondii) is a neurotropic parasite that is associated with various neuropsychiatric disorders. Rodents infected with T. gondii display a plethora of behavioural alterations, and Toxoplasma infection in humans has been strongly associated with disorders such as schizophrenia, in which impaired social behaviour is an important feature. Elucidating changes at the cellular level relevant to neuropsychiatric conditions can lead to effective therapies. Here, we compare changes in behaviour during an acute and chronic T. gondii infection in female mice. Further, we notice that during chronic phase of infection, mice display impaired sociability when exposed to a novel conspecific. Also, we show that T. gondii infected mice display impaired short-term social recognition memory. However, object recognition memory remains intact. Using c-Fos as a marker of neuronal activity, we show that infection leads to an impairment in neuronal activation in the medial prefrontal cortex, hippocampus as well as the amygdala when mice are exposed to a social environment and a change in functional connectivity between these regions. We found changes in synaptic proteins that play a role in the process of neuronal activation such as synaptophysin, PSD-95 and changes in downstream substrates of cell activity such as cyclic AMP, phospho-CREB and BDNF. Our results point towards an imbalance in neuronal activity that can lead to a wider range of neuropsychiatric problems upon T. gondii infection.

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Section: Discussionsupporting

confidence: 66%

Impaired social behaviour and molecular mediators of associated neural circuits during chronicToxoplasma gondiiinfection in female mice

Tyebji

Seizova

Garnham

et al. 2018

Preprint

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“…Similar to our findings, Finlay et al show that genetic removal of NMDRs from the dorso-lateral hippocampus (inclusive of CA2 and CA3 neurons) in adulthood resulted in no effect on social novelty preference, which requires social memory (Finlay, Dunham et al 2015). Furthermore, although pyramidal CA2 neurons do not respond to standard long-term potentiation inducing protocols, it was recently observed that input-timing dependent plasticity can occur, but that this change in pyramidal neuron response is driven by long-term depression of adjacent parvalbumin (PV) interneurons in the CA2 region (Dudek, Alexander et al 2016, Leroy, Brann et al 2017). Blocking delta opioid receptors, which are found on PV interneurons in the CA2, was able to block the depression in the PV interneurons, the potentiation in the pyramidal neurons and short-term social memory (Leroy, Brann et al 2017).…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor in vasopressin 1b neurons is not required for short-term social memory, object memory or aggression

Avram

Fastman

Cymerblit‐Sabba

et al. 2019

Preprint

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The vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including aggression, social learning and memory. Genetic removal of Avpr1b from mouse models results in deficits in aggression and short-term social recognition in adults. Avpr1b gene expression is highly enriched in the pyramidal neurons of the hippocampal cornu ammonis 2 (CA2) region. Activity of the hippocampal CA2 has been shown to be required for normal short-term social recognition and aggressive behaviors. Vasopressin acts to enhance synaptic responses of CA2 neurons through a NMDA-receptor dependent mechanism. Genetic removal of the obligatory subunit of the NMDA receptor (Grin1) within distinct hippocampal regions impairs non-social learning and memory. However, the question of a direct role for NMDA receptor activity in Avpr1b neurons to modulate social behavior remains unclear. To answer this question, we first created a novel transgenic mouse line with Cre recombinase knocked into the Avpr1b coding region to genetically target Avpr1b neurons. We confirmed this line has dense Cre expression throughout the dorsal and ventral CA2 regions of the hippocampus, along with scattered expression within the caudate-putamen and olfactory bulb. Conditional removal of the NMDA receptor was achieved by crossing our line to an available floxed Grin1 line. The resulting mice were measured on a battery of social and memory behavioral tests. Surprisingly, we did not observe any differences between Avpr1b-Grin1 knockout mice and their wildtype siblings. We conclude that mice without typical NMDA receptor function in Avpr1b neurons can develop normal aggression as well as short-term social and object memory performance.Significance StatementActivity of neurons that express vasopressin 1b receptor are essential for aggressive and social recognition behaviors. We created a novel transgenic mouse to allow selective targeting of vasopressin 1b neurons. Our studies indicate that NMDA receptor expression in vasopressin 1b neurons (including most CA2 neurons) are not required for development of the typical expression of aggression or recognition memory. Thus, CA2 neurons may have a unique way of incorporating novel stimuli into memory that deserves further investigation.

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“…Given the known layered organization of entorhinal, septal and supramammillary inputs at SLM and SO (Soussi et al, 2010;Joshi et al 2017), our data suggest distal CA2 cells may be biased towards extra-hippocampal theta generators, while proximal CA2 cells rather follow intra-hippocampal CA3 influences. Proximodistal differences of I/E balance and unique plasticity properties of different pathways may further contribute (Piskorowski and Chevaleyre 2013;Nasrallah et al 2016;Dasgupta et al, 2017;Leroy et al, 2017;Sun et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…The CA2 hippocampal region has distinctive molecular, physiological and connectivity properties . CA2 pyramidal cells respond vigorously to direct entorhinal inputs from layer II stellate cells Leroy et al 2017). In addition, they receive a direct mossy fiber connection from granule cells and contribute to a parallel trisynaptic circuit to deep CA1 sublayers (Kohara et al, 2014;Sun et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Instead, memory for a familiar conspecific is affected. Such a role in social memory may reflect not only specific features of CA2 (Leroy et al 2017), but also downstream effects over deep CA1 pyramidal cells (Okuyama et al 2016). Possibly, CA2 is instrumental in balancing microcircuit operation across different brain systems, but the mechanisms are ignored.…”

Section: Introductionmentioning

confidence: 99%

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Proximodistal organization of the CA2 hippocampal area

Fernández-Lamo¹,

Gómez-Domínguez²,

Sánchez-Aguilera³

et al. 2018

Preprint

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Competitividad (MINECO) to LMP (BFU2015-66887-R) and the Fundación Tatiana Perez de Guzman el Bueno. DGD and MV were supported by a PhD fellowship from the Spanish Ministry of Economy (BES-2013-064171) and from the Ministry of Education, Culture and Sports (FPU12/03776), respectively. We thank to the Deisseroth lab for sharing their optogenetic constructs. VGAT-Venus transgenic rats were generated by Drs. Y. Yanagawa, M. Hirabayashi, and Y.Kawaguchi at the National Institute for Physiological Sciences (Okazaki, Japan) using pCS2-Venus provided by Dr. A. Miyawaki. VGAT line progenitors were provided by the National Bioresource Project Rat (Kyoto, Japan) 2The proximodistal axis is considered a major organizational principle of the hippocampus. Interfacing between the hippocampus and other brain systems, the CA2 region apparently breaks this rule. Apart from its specific role in social memory, CA2 has been involved in temporal and contextual memory but mechanisms remain elusive. Here, we used intracellular and extracellular recordings followed by neurochemical identification of single-cells to evaluate CA2 and surrounding areas in the rat. We found marked proximodistal trends of synaptic activity, as well as in subthreshold membrane potentials and phase-locked firing coupled to theta and gamma oscillations. Opposite proximodistal correlations between membrane potential fluctuations and theta sinks and sources at different layers revealed influences from up to three different generators. CA2 memory engrams established after a social memory task reflected these trends. We suggest that the structure and function of CA2 is segregated along the proximodistal hippocampal axis.

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Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory

Cited by 78 publications

References 60 publications

Impaired social behaviour and molecular mediators of associated neural circuits during chronicToxoplasma gondiiinfection in female mice

Impaired social behaviour and molecular mediators of associated neural circuits during chronicToxoplasma gondiiinfection in female mice

NMDA receptor in vasopressin 1b neurons is not required for short-term social memory, object memory or aggression

Proximodistal organization of the CA2 hippocampal area

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