EphrinB2 regulates VEGFR2 during dendritogenesis and hippocampal circuitry development

Harde, Eva; Nicholson, LaShae; Cuadrado, Beatriz Furones; Bissen, Diane; Wigge, Sylvia; Urban, Severino; Segarra, Marta; Almodóvar, Carmen Ruiz de; Acker‐Palmer, Amparo

doi:10.7554/elife.49819

“…Changes in the AMPA/NMDA ratio and synaptic integration properties are often accompanied by changes in neuronal morphology and dendritic spine complexity, which can be indicative of structural LTP (sLTP) (58)(59)(60)(61)(62). To investigate this possibility, VMHvl Esr1 neurons which exhibited an increase in the AMPA/NMDA ratio and synaptic integration in acute slice preparations were filled with neurobiotin, and super-resolution images for reconstruction were obtained using the Airyscanning technique in a ZEISS LSM 880 (63,64).…”

Section: Resultsmentioning

confidence: 99%

Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

Stagkourakis

¹

,

Spigolon

²

,

Liu

³

et al. 2020

Preprint

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All animals can perform certain survival behaviors without prior experience, suggesting a “hard wiring” of underlying neural circuits. Experience, however, can alter the expression of innate behaviors. Where in the brain and how such plasticity occurs remains largely unknown. Previous studies have established the phenomenon of “aggression training,” in which the repeated experience of winning successive aggressive encounters across multiple days leads to increased aggressiveness. Here we show that this procedure also leads to long-term potentiation (LTP) at an excitatory synapse, derived from the Anterior Hippocampus/Posterior Medial amygdala (AHiPM), onto estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate further that the optogenetic induction of such LTP in vivo facilitates, while optogenetic long-term depression (LTD) diminishes, the behavioral effect of aggression training, implying a causal role for potentiation at AHiPM➔VMHvlEsr1 synapses in mediating the effect of this training. Interestingly, ∼25% of inbred C57BL/6 mice fail to respond to aggression training. We show that these individual differences are correlated both with lower levels of testosterone, relative to mice that respond to such training, and with a failure to exhibit LTP in vivo after aggression training. Administration of exogenous testosterone to such non-aggressive mice restores both behavioral and physiological plasticity in vivo. Together, these findings reveal that LTP at a hypothalamic circuit node mediates a form of experience-dependent plasticity in an innate social behavior, and a potential hormone-dependent basis for individual differences in such plasticity among genetically identical mice.Significance StatementModification of instinctive behaviors occurs through experience, yet the mechanisms through which this happens have remained largely unknown. Recent studies have shown that potentiation of aggression, an innate behavior, can occur through repeated winning of aggressive encounters. Here we show that synaptic plasticity at a specific excitatory input to a hypothalamic cell population is correlated with, and required for, the expression of increasingly higher levels of aggressive behavior following successful aggressive experience. We additionally show that the amplitude and persistence of long-term potentiation at this synapse are influenced by serum testosterone, administration of which can normalize individual differences among genetically identical inbred mice, in the expression of intermale aggression.

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“…Changes in the AMPA/NMDA ratio and synaptic integration properties are often accompanied by changes in neuronal morphology and dendritic spine complexity, which can be indicative of structural LTP (sLTP) (33). To investigate this possibility, VMHvl Esr1 neurons from which the AMPA/NMDA measurements were acquired were filled with neurobiotin, and superresolution images for reconstruction were obtained using the Airyscanning technique in a ZEISS LSM 880 (34).…”

Section: Plasticity At a Hypothalamic Synapse Following Aggression Trmentioning

confidence: 99%

Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

Stagkourakis

¹

,

Spigolon

²

,

Liu

³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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All animals can perform certain survival behaviors without prior experience, suggesting a “hard wiring” of underlying neural circuits. Experience, however, can alter the expression of innate behaviors. Where in the brain and how such plasticity occurs remains largely unknown. Previous studies have established the phenomenon of “aggression training,” in which the repeated experience of winning successive aggressive encounters across multiple days leads to increased aggressiveness. Here, we show that this procedure also leads to long-term potentiation (LTP) at an excitatory synapse, derived from the posteromedial part of the amygdalohippocampal area (AHiPM), onto estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate further that the optogenetic induction of such LTP in vivo facilitates, while optogenetic long-term depression (LTD) diminishes, the behavioral effect of aggression training, implying a causal role for potentiation at AHiPM→VMHvlEsr1 synapses in mediating the effect of this training. Interestingly, ∼25% of inbred C57BL/6 mice fail to respond to aggression training. We show that these individual differences are correlated both with lower levels of testosterone, relative to mice that respond to such training, and with a failure to exhibit LTP after aggression training. Administration of exogenous testosterone to such nonaggressive mice restores both behavioral and physiological plasticity. Together, these findings reveal that LTP at a hypothalamic circuit node mediates a form of experience-dependent plasticity in an innate social behavior, and a potential hormone-dependent basis for individual differences in such plasticity among genetically identical mice.

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“…In the accompanying manuscript (Harde et al, 2019), we show that ephrinB2 is expressed in hippocampal neurons during development and that its expression is required for VEGFR2 internalization and VEGF-induced dendritic branching. We therefore tested whether VEGFR2 internalization is required for VEGF-induced axon branching and whether ephrinB2 would also play a role in regulating axon branching.…”

Section: Resultsmentioning

confidence: 81%

“…To investigate whether VEGFR2 is crucial for the development of hippocampal neurons, we genetically deleted the gene encoding VEGFR2 ( Kdr ) in the nervous system by crossing Kdr lox/- mice (Haigh et al, 2003) with the Nestin-cre mouse line (Tronche et al, 1999). PCR analysis and Western blotting of lysates from isolated hippocampal neurons confirmed the absence of VEGFR2 mRNA and protein in hippocampal neurons of Nestin-cre + ;Kdr lox/- animals compared to Nestin-cre - ;Kdr lox/- littermates (from hereon termed Nes-cre;Kdr lox/- and control, respectively) (see accompanying manuscript Harde et al, 2019) We first characterized the cytoarchitecture of the entire hippocampus in Nes-cre;Kdr lox /- mice. We labeled brain sections of P10 Nes-cre;Kdr lox/- and control mice with TO-PRO-3 (labels all nuclei), NeuN (labels neuronal nuclei) and L1 (labels axonal tracks) and analyzed the gross morphology of the hippocampus, the number of hippocampal neurons, the size of the CA3 area and the axonal tracks.…”

Section: Resultsmentioning

confidence: 90%

VEGF/VEGFR2 signaling regulates hippocampal axon branching during development

Luck

¹

,

Urban

²

,

Karakatsani

³

et al. 2019

eLife

Self Cite

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Axon branching is crucial for proper formation of neuronal networks. Although originally identified as an angiogenic factor, VEGF also signals directly to neurons to regulate their development and function. Here we show that VEGF and its receptor VEGFR2 (also known as KDR or FLK1) are expressed in mouse hippocampal neurons during development, with VEGFR2 locally expressed in the CA3 region. Activation of VEGF/VEGFR2 signaling in isolated hippocampal neurons results in increased axon branching. Remarkably, inactivation of VEGFR2 also results in increased axon branching in vitro and in vivo. The increased CA3 axon branching is not productive as these axons are less mature and form less functional synapses with CA1 neurons. Mechanistically, while VEGF promotes the growth of formed branches without affecting filopodia formation, loss of VEGFR2 increases the number of filopodia and enhances the growth rate of new branches. Thus, a controlled VEGF/VEGFR2 signaling is required for proper CA3 hippocampal axon branching during mouse hippocampus development.

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EphrinB2 regulates VEGFR2 during dendritogenesis and hippocampal circuitry development

Cited by 21 publications

References 79 publications

Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

Experience-dependent plasticity in an innate social behavior is mediated by hypothalamic LTP

VEGF/VEGFR2 signaling regulates hippocampal axon branching during development

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