Adenosine A2A Receptors Control Glutamatergic Synaptic Plasticity in Fast Spiking Interneurons of the Prefrontal Cortex

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.

Adenosine A1 and A2A receptors differently control synaptic plasticity in the mouse dorsal and ventral hippocampus

“…In contrast to this controversial role of A 1 R on LTP, our findings clearly identified a selective role of A 2A R to control synaptic plasticity, without any evident impact on basal synaptic transmission, as also occurs in different brain regions (d'Alcantara et al, 2001;Rebola et al, 2008;Simões et al, 2016;Viana da Silva et al, 2016;Kerkhofs et al, 2018). The impact of A 2A R is more evident in DH than in VH, in accordance with the near double density of A 2A R in synapses of DH compared with VH and matches the selective A 2A R-metabotropic glutamate receptor 5 interaction controlling NMDA receptors in DH (Kouvaros and Papatheodoropoulos, 2016a).…”

“…In keeping with the robust effect of A 2A R in the control of LTP in the hippocampus (Rebola et al, ; Costenla et al, ; Viana da Silva et al, ) and in different brain areas (d’Alcantara et al, ; Simões et al, ; Kerkhofs et al, ), the A 2A R antagonist SCH58261 (50 nM) decreased LTP amplitude in DH (control: 64.7 ± 9.6% above basal; SCH58261: 37.6 ± 4.3%, above basal. n = 6–7, p < 0.05, Mann–Whitney test) (Fig.…”

Synaptic Plasticity in Cortical Inhibitory Neurons: What Mechanisms May Help to Balance Synaptic Weight Changes?

“…The following studies provide further evidence for plasticity in FS and non-FS interneurons but did not investigate its NMDA dependence. In the medial prefrontal cortex, theta-burst stimulation induced LTP in FS cells (Kerkhofs et al, 2018 ). In the visual cortex, repetitive pairing of presynaptic stimulation with bursts of postsynaptic spikes can induce long-term plasticity in both FS and non-FS cells from layers 2/3, 4, and 5 (Chistiakova et al, 2019 ).…”

Adenosine A2A receptors modulate the dopamine D2 receptor‐mediated inhibition of synaptic transmission in the mouse prefrontal cortex

“…Electrophysiological recordings of excitatory transmission in the medial PFC were carried out as previously described (Kerkhofs et al ., ). Briefly, individual slices were transferred to a submerged recording chamber and continuously superfused at a rate of 2 mL/min with gassed aCSF kept at room temperature.…”

“…A 2A R have received particular attention to manage neuropsychiatric disorders (Cunha et al ., ). A 2A R are present in the PFC (Pandolfo et al ., ; Kerkhofs et al ., ) and control different PFC‐dependent functions such as attention (Higgins et al ., ), cognition (Kadowaki Horita et al ., ), working memory (Zhou et al ., ) and decision‐making (Pardo et al ., ) that are also tightly controlled by dopamine (Seamans & Yang, ).…”