MOLECULAR MECHANISMS UNDERLYING TRKB/A2A CROSSTALK

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Neuroexcitability control by adenosine and BDNF at the adult hippocampus

Publication . Oliveira, Mariana Colino de, 1988-; Sebastião, Ana Maria, 1958-

The traditional view of neuronal communication involves a network of neurons communicating through neurotransmitters, which either lead to neuronal depolarization or hyperpolarization. However, the overall output is also determined by the presence of neuromodulators. These are molecules able to alter the function of a circuitry by modifying the properties of synaptic conductance and the intrinsic membrane properties of individual neurons. Neuromodulators are thus critical in the regulation of synaptic transmission and plasticity. Adenosine and Bain-Derived Neurotrophic Factor (BDNF) are two well-known modulators of the central nervous system. BDNF induces pre- and post-synaptic changes that lead to a facilitation of glutamatergic transmission through its high affinity receptor, TrkB receptor. However, BDNF influence upon GABAergic transmission in the adult brain is poorly understood. I now evaluated whether BDNF modulates GABAergic transmission in the adult hippocampus. Evoked and spontaneous synaptic currents were recorded from CA1 pyramidal cells in acute hippocampal slices from young adult rat brains (6 to 10 weeks-old). BDNF (10-100 ng/mL) increased miniature inhibitory post-synaptic currents (mIPSCs) frequency, but not amplitude, as well as increased the amplitude of inhibitory post-synaptic currents (IPSCs) evoked by afferent stimulation. The facilitatory action of BDNF upon GABAergic transmission was lost in the presence of a Trk inhibitor (K252a, 200 nM), but not upon p75NTR blockade (Anti-p75NTR IgG, 50 μg/mL). Since adenosine A2A receptor is an upstream regulator of TrkB activity, a putative influence of this receptor was also investigated. The facilitatory action of BDNF onto GABAergic transmission was also prevented upon adenosine A2A receptor antagonism (SCH 58261, 50 nM). I thus concluded that BDNF facilitates GABAergic signaling at the adult hippocampus via a pre-synaptic mechanism that depends on TrkB and adenosine A2A receptor activation. Adenosine net effect is to inhibit synaptic activity through the binding to the adenosine A1 receptor (A1R). Despite the low expression of the adenosine A2A receptor (A2AR), through its activation, adenosine may also enhance synaptic strength. Astrocytic Adenosine kinase (ADK) accounts as the major contributor for adenosine metabolic clearance from synaptic cleft, determining the intra- and extracellular concentrations of adenosine. Accordingly, ADK up-regulation correlates with decreased adenosine levels, with consequent impaired A1R-mediated signaling and increased susceptibility to epileptic seizures. Surprisingly, mice lacking ADK expression in the entire brain develop progressive epilepsy with stress-induced seizures in an age-dependent way. They present spontaneous convulsive seizures by the age of 5 months old, until their first year old, when they become asymptomatic. Functional and biochemical studies were performed in order to characterize adenosine and BDNF receptors in pre-symptomatic (2 months old), symptomatic (5 to 8 months old) and post-symptomatic (over 1 year old) mice. ADK knockout mice at all ages demonstrated enhanced adenosine levels around synapses, but impaired A1R receptor function of synaptic transmission with concomitant lower expression protein levels of the receptor. Lack of A1R inhibitory signaling is observed independently of animal age, so it cannot account for the epileptic phenotype, despite it may account for a higher neuronal excitability. However, adenosine A2AR and BDNF signaling undergo a shift from the pre- to the symptomatic stage. In mice lacking ADK, A2AR activation and BDNF signaling is augmented leading to enhanced synaptic plasticity, which may play a role in the triggering of the seizure phenotype. Accordingly, A2AR and BDNF are overexpressed in epileptic mice lacking Adk in the brain. This work besides suggesting that A2AR and BDNF exacerbated signaling have pro-epileptic affects, provide evidence that ADK may present a genetic risk for the development of epilepsy since it has intrinsic effects onto brain activity, but also offers new opportunities for the development of pharmacologic tools for seizure disorders.

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Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/73276/2010