Dopaminergic Neuromodulation of Spike Timing Dependent Plasticity in Mature Adult Rodent and Human Cortical Neurons

Abstract

Synapses in the cerebral cortex constantly change and this dynamic property regulated by the action of neuromodulators such as dopamine (DA), is essential for reward learning and memory. DA modulates spike-timing-dependent plasticity (STDP), a cellular model of learning and memory, in juvenile rodent cortical neurons. However, it is unknown whether this neuromodulation also occurs at excitatory synapses of cortical neurons in mature adult mice or in humans. Cortical layer V pyramidal neurons were recorded with whole cell patch clamp electrophysiology and an extracellular stimulating electrode was used to induce STDP. DA was either bath-applied or optogenetically released in slices from mice. Classical STDP induction protocols triggered non-hebbian excitatory synaptic depression in the mouse or no plasticity at human cortical synapses. DA reverted long term synaptic depression to baseline in mouse via dopamine 2 type receptors or elicited long term synaptic potentiation in human cortical synapses. Furthermore, when DA was applied during an STDP protocol it depressed presynaptic inhibition in the mouse but not in the human cortex. Thus, DA modulates excitatory synaptic plasticity differently in human vs. mouse cortex. The data strengthens the importance of DA in gating cognition in humans, and may inform on therapeutic interventions to recover brain function from diseases.

Long-term memory, synaptic plasticity and dopamine in rodent medial prefrontal cortex: Role in executive functions

“…Pharmacological modulation of D2 receptor activity did not affect plasticity directly, but only indirectly via inhibition of GABA release by interneurons (Chiu et al, 2010 ; Xu and Yao, 2010 ). In the presence of GABA, t-LTD or no change have been observed at almost all tested intervals (in both young adult and mature mice, Louth et al, 2021 ). Optogenetic activation of VTA DA fibers blocked t-LTD and this modulatory effect was abolished in the presence of the D2 receptor antagonist, but was not affected by the D1 receptor antagonist (Louth et al, 2021 ).…”

“…In the presence of GABA, t-LTD or no change have been observed at almost all tested intervals (in both young adult and mature mice, Louth et al, 2021 ). Optogenetic activation of VTA DA fibers blocked t-LTD and this modulatory effect was abolished in the presence of the D2 receptor antagonist, but was not affected by the D1 receptor antagonist (Louth et al, 2021 ). The blockade of t-LTD by D2 receptors is consistent with the evidence of D2-mediated GABA suppression by DA acting by inhibiting its presynaptic release (Xu and Yao, 2010 ).…”

“…Finally, regulation of long-term plasticity by inhibitory GABAergic transmission has been demonstrated in a number of studies (Couey et al, 2007;Huang et al, 2007;Chiu et al, 2010;Xu and Yao, 2010;Louth et al, 2021). Often the same neuromodulator acts in a cooperative manner on both glutamatergic and GABAergic transmission to influence plasticity (Couey et al, 2007;Xu and Yao, 2010).…”

“…A number of studies applied STDP protocols to study prefrontal long-term plasticity in rats and mice, including its modulation by DA, as well as by other neuromodulators (Couey et al, 2007 ; Xu and Yao, 2010 ; Goriounova and Mansvelder, 2012 ; Zaitsev and Anwyl, 2012 ; Ruan et al, 2014 ; Louth et al, 2021 ). These experiments have shown that regulation of plasticity by pre-post timings in mPFC is different from that in the classical experiments, since in the absence of exogenous DA and with blocked inhibitory (GABA) receptors, LTP was induced by pre-post stimulation at Δ t = +5, +10 ms, whereas no plasticity could be induced either by Δ t = +30 ms or Δ t = −30 ms. An application of a high DA concentration (20–100 μM) during pairing extended t-LTP portion of STDP to all the tested time intervals (Xu and Yao, 2010 ; Ruan et al, 2014 ).…”

Calcium and Spike Timing-Dependent Plasticity

“…This may constitute an additional limitation to the transposition of the results observed in vitro . Several studies suggest that the capacity to induce t-LTD decreases with age (Banerjee et al, 2009 ; Verhoog et al, 2013 ) although a recent study has shown t-LTD at cortical layer V synapses in adult mice following pre-before-post protocol (Louth et al, 2021 ). Similarly, induction of t-LTD by a STDP protocol in the somato-sensory cortex of adult rats by pairing postsynaptic spikes and subthreshold whisker deflection is relatively frequent whereas induction of t-LTP in the same preparation is rare (Jacob et al, 2007 ).…”