A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior

Abstract

Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-D-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic sites by increasing the surface dynamics of these receptors within the membrane. Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural cells impairs hippocampal-dependent synaptic plasticity and consolidation of emotional memory. These findings demonstrated the direct implication of VEGF signaling in neurons via VEGFR2 in proper synaptic function. They highlight the potential of VEGF as a key regulator of GluNR synaptic function and suggest a role for VEGF in new therapeutic approaches targeting GluNR in depression.

Blood-brain barrier regulation in psychiatric disorders

“…Cerebral vascularisation is mediated by VEGF and VEGF significantly contributes to angiogenesis by stimulating neovascularisation and is intimately involved in the regulation of CBF. Additionally, VEGF has a key role in neurophysiology as suppression of neural VEGFR2 impairs hippocampal-dependent synaptic plasticity and long-term potentiation and consolidation of emotional memory in mice [121]. Studies specifically focussing on other BBB molecular components such as tight junction proteins have been limited.…”

Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1

“…Angiogenesis is stimulated by vascular endothelial growth factor A (VEGFA)10, which also directly enhances neurogenesis and synaptic function11; however, the initial molecular signal that leads to increased cerebral VEGFA in response to exercise has not been determined. Exercise at high intensity, causing lactate from active skeletal muscles to accumulate in the blood, and lactate injections have previously been found to increase brain expression of VEGFA12, but the mechanism is unknown.…”

Nascidos Para Correr: A Importância Do Exercício Para a Saúde Do Cérebro

“…Além disso, a infusão periférica de IGF-1 também aumenta a neurogênese no cérebro de animais adultos, além de reverter a redução neuronal relacionada ao envelhecimento 45 . Deste modo, muitos autores concluem que as alterações vasculares no cérebro em consequência do exercício podem ser mediadas por fatores como o IGF e VEGF [44][45][46][47][48][49] . Os efeitos de longo prazo do exercício parecem resultar de diferentes respostas e adaptações, comparados com os efeitos do exercício agudo.…”

“…O exercício físico vem sendo apontado como uma eficaz estratégia não-farmacológica, cujo efeito protetor retarda o declínio cognitivo em consequência do envelhecimento [90][91][92] . Estudos em animais verificaram que o exercício de corrida voluntária aumenta a expressão de BNDF (fator neurotrófico derivado do cérebro), IGF1 (fator de crescimento semelhante a insulina tipo 1) e VEGF (Fator de crescimento endotelial vascular) [44][45][46][47][48][49] . Como já mencionado, o BNDF é um importante regulador da plasticidade sináptica e níveis diminuídos dessa proteína causam redução da plasticidade sináptica em áreas do cérebro afetadas durante o processo de envelhecimento 11 .…”