Selective expression of a constitutively active erythropoietin receptor in <scp>GABA</scp>ergic neurons alters hippocampal network properties without affecting cognition

Wüstefeld, Liane; Winkler, Daniela; Janc, Oliwia A.; Hassouna, Imam; Ronnenberg, Anja; Ostmeier, Katrin; Müller, Michael; Ehrenreich, Hannelore; Wojcik, Sonja M.

doi:10.1111/jnc.13445

Cited by 5 publications

(7 citation statements)

References 35 publications

(38 reference statements)

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“…6A ). This difference has also been reported in other studies 47 , 48 ; however, the gender difference in repetitive behaviors remains unclear. For self-grooming, although the female KO group showed increased self-grooming, the female heterozygous (Het) group did not exhibit increased self-grooming (Fig.…”

Section: Discussionsupporting

confidence: 83%

Deficiency of a brain-specific chemokine-like molecule, SAM3, induces cardinal phenotypes of autism spectrum disorders in mice

Kim

Lee

Choi

et al. 2017

Sci Rep

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Chemokines are small secreted signaling proteins produced by a broad range of cells, including immune cells. Several studies have recently suggested potential roles of chemokines and their receptors in the pathophysiology of autism spectrum disorders (ASDs). SAM3 is a novel brain-specific chemokine-like molecule with an unknown physiological function. We explored the relevance of chemokines in the development of ASD in mice, with a focus on SAM3. We generated Sam3 gene knockout (KO) mice and characterized their behavioral phenotypes, with a focus on those relevant to ASD. Sam3-deficient mice displayed all three core phenotypes of ASD: impaired responses to social novelty, defects in social communication, and increased repetitive behavior. In addition, they showed increased anxiety. Interestingly, gender differences were identified for several behaviors: only male Sam3 KO mice exhibited increased anxiety and increased repetitive behaviors. Sam3 KO mice did not exhibit changes in other behaviors, including locomotor activities, fear learning and memory, and object recognition memory. These findings indicate that a deficiency of SAM3, a novel brain-specific chemokine-like molecule, may lead to the pathogenesis of ASDs and suggest the possibility that SAM3, a soluble factor, could be a novel therapeutic target for ASD treatment.

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Section: Discussionsupporting

confidence: 83%

Deficiency of a brain-specific chemokine-like molecule, SAM3, induces cardinal phenotypes of autism spectrum disorders in mice

Kim

Lee

Choi

et al. 2017

Sci Rep

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“…(iii) Even more compellingly, the above-cited study on transgenic EPO expression in brain [ 29 ] and (iv) non-hematopoietic EPO analogues [ 32 – 37 ] have been further key arguments for EPO actions on brain in absence of blood effects. (v) Moreover, boosted cognition and neuroplasticity of mice expressing constitutively active EPOR in glutamatergic pyramidal neurons [ 38 ], but not in GABAergic interneurons [ 39 ], suggested a central role of these neurons for EPO effects on cognition, independent of hematopoiesis.…”

Section: Separating Epo Effects On Brain From Hematopoiesismentioning

confidence: 99%

“…In a mouse model of traumatic brain injury, we saw that early treatment with rhEPO prevented consequences of secondary neurodegeneration, i.e., progressive brain atrophy and cognitive decline [ 25 , 97 ], reduced the increase in injury-induced microglia and dampened their motility [ 98 , 99 ]. Reflecting the high - but still poorly understood - complexity of the brain EPO system, also interneurons [ 39 , 100 ], oligodendrocytes, their precursors (OPC) [ 45 ], astrocytes, endothelial cells and pericytes express EPO and EPOR, at least in disease [ 6 , 10 ], and EPO not only traverses the blood-brain-barrier (BBB), but influences BBB function, immune cell transmigration, angiogenesis, and cerebral blood flow [ 31 , 101 – 103 ].…”

Section: Delineating the Multifaceted And Multicellular Brain Epo Systemmentioning

confidence: 99%

“…In a transgenic mouse line that constitutively overexpresses neuronal EPO from early development on, stimulation of postnatal GABAergic maturation and an elevation of hippocampal GABA-immunoreactive neurons was reported, together with increase in interneurons expressing parvalbumin, somatostatin and neuropeptide Y [ 100 ]. Whereas constitutively active EPOR in GABAergic neurons changed hippocampal network properties, cognition was not affected, suggesting that the effect of EPO on cognition is dominated by its effect on the glutamatergic system [ 39 ]. Much more work is needed to fully understand the impact of EPO on the inhibitory circuitry.…”

Section: Delineating the Multifaceted And Multicellular Brain Epo Systemmentioning

confidence: 99%

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Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Ehrenreich¹,

Garcia-Agudo²,

Steixner-Kumar³

et al. 2022

Mol Psychiatry

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PrefaceExecutive functions, learning, attention, and processing speed are imperative facets of cognitive performance, affected in neuropsychiatric disorders. In clinical studies on different patient groups, recombinant human (rh) erythropoietin (EPO) lastingly improved higher cognition and reduced brain matter loss. Correspondingly, rhEPO treatment of young rodents or EPO receptor (EPOR) overexpression in pyramidal neurons caused remarkable and enduring cognitive improvement, together with enhanced hippocampal long-term potentiation. The ‘brain hardware upgrade’, underlying these observations, includes an EPO induced ~20% increase in pyramidal neurons and oligodendrocytes in cornu ammonis hippocampi in the absence of elevated DNA synthesis. In parallel, EPO reduces microglia numbers and dampens their activity and metabolism as prerequisites for undisturbed EPO-driven differentiation of pre-existing local neuronal precursors. These processes depend on neuronal and microglial EPOR. This novel mechanism of powerful postnatal neurogenesis, outside the classical neurogenic niches, and on-demand delivery of new cells, paralleled by dendritic spine increase, let us hypothesize a physiological procognitive role of hypoxia-induced endogenous EPO in brain, which we imitate by rhEPO treatment. Here we delineate the brain EPO circle as working model explaining adaptive ‘brain hardware upgrade’ and improved performance. In this fundamental regulatory circle, neuronal networks, challenged by motor-cognitive tasks, drift into transient ‘functional hypoxia’, thereby triggering neuronal EPO/EPOR expression.

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“…In vitro field recordings of murine hippocampal slices. Data from 73 are analyzed comparing carbachol induced gamma oscillations in wt mice and a constitutively active form of the erythropoietin receptor in GABAergic neurons (VEPOR +/+ ) 73 . Field oscillations were induced with 20 μM carbachol (Sigma-…”

Section: Equation 1 (Modulation See Supplement)mentioning

confidence: 99%

Quantifying and modelling non-local information processing of associative brain regions

Balkenhol¹,

García-Prada²,

Ehrenreich

et al. 2019

Preprint

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Short abstract (150 words)Brain world representation emerges not by philosophy but from integrating simple followed by more complex actions (due to drives, instincts) with sensory feedback and inputs such as rewards. Our simulation provides this world representation holistically by identical information encoded as holographic wave patterns for all associative cortex regions. Observed circular activation in cell culture experiments provides building blocks from which such an integrative circuit can evolve just by excitation and inhibition transfer to neighbouring neurons. Large-scale grid-computing of the simulation brought no new emergent phenomena but rather linear gains and losses regarding performance. The circuit integrates perceptions and actions. The resulting simulation compares well with data from electrophysiology, visual perception tasks, and oscillations in cortical areas. Non-local, wave-like information processing in the cortex agrees well with EEG observations such as cortical alpha, beta, and gamma oscillations. Non-local information processing has powerful emergent properties, including key features of conscious information processing.

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Selective expression of a constitutively active erythropoietin receptor in GABAergic neurons alters hippocampal network properties without affecting cognition

Cited by 5 publications

References 35 publications

Deficiency of a brain-specific chemokine-like molecule, SAM3, induces cardinal phenotypes of autism spectrum disorders in mice

Deficiency of a brain-specific chemokine-like molecule, SAM3, induces cardinal phenotypes of autism spectrum disorders in mice

Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Quantifying and modelling non-local information processing of associative brain regions

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