Abstract
Adenosine A2A receptors (A2AR) are activated upon increased synaptic activity to assist in the implementation of long-term plastic changes at synapses. While it is reported that A2AR are involved in the control of prefrontal cortex (PFC)-dependent behavior such as working memory, reversal learning and effort-based decision making, it is not known whether A2AR control glutamatergic synapse plasticity within the medial PFC (mPFC). To elucidate that, we tested whether A2AR blockade affects long-term plasticity (LTP) of excitatory post-synaptic potentials in pyramidal neurons and fast spiking (FS) interneurons in layer 5 of the mPFC and of population spikes. Our results show that A2AR are enriched at mPFC synapses, where their blockade reversed the direction of plasticity at excitatory synapses onto layer 5 FS interneurons from LTP to long-term depression, while their blockade had no effect on the induction of LTP at excitatory synapses onto layer 5 pyramidal neurons. At the network level, extracellularly induced LTP of population spikes was reduced by A2AR blockade. The interneuron-specificity of A2AR in controlling glutamatergic synapse LTP may ensure that during periods of high synaptic activity, a proper excitation/inhibition balance is maintained within the mPFC.
Highlights
The prefrontal cortex (PFC) is involved in the control of cognitive and executive functions, such as decision making, working memory, inhibitory control, attention, and behavioral flexibility (Dalley et al, 2004; Euston et al, 2013)
We found that A2A receptors (A2AR) are enriched at medial PFC (mPFC) synapses, where A2AR blockade shifts the direction of plasticity at excitatory synapses onto layer 5 fast spiking (FS) interneurons from long-term plasticity (LTP) to long-term depression (LTD), while it is ineffective at excitatory synapses onto layer 5 pyramidal neurons and reduces plasticity at the network level
We show that in the mPFC, A2AR control LTP at excitatory synapses onto fast-spiking interneurons rather than onto pyramidal neurons
Summary
The prefrontal cortex (PFC) is involved in the control of cognitive and executive functions, such as decision making, working memory, inhibitory control, attention, and behavioral flexibility (Dalley et al, 2004; Euston et al, 2013). The flexible regulation of these types of behavior makes it possible to properly respond to a changing environment (Arnsten, 2009). Such flexibility is thought to require plastic changes in the strength of synaptic connections (Kandel, 1976; Mayford et al, 2012), which is heavily dependent on the action of several neuromodulators (Pawlak et al, 2010; Bloem et al, 2014; Dembrow and Johnston, 2014). Its actions are mediated by a balanced activation of the inhibitory A1 receptors (A1R) and the facilitatory A2A receptors (A2AR) (Cunha, 2008), which act predominantly on glutamatergic and on. While A1R control basal synaptic transmission, A2AR are selectively engaged in events where long-term potentiation (LTP) is induced (d’Alcantara et al, 2001; Rebola et al, 2008; Simões et al, 2016)
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