Altered Heterosynaptic Plasticity Impairs Visual Discrimination Learning in Adenosine A1 Receptor Knock-Out Mice

Abstract

Theoretical and modeling studies demonstrate that heterosynaptic plasticity -changes at synapses inactive during induction -facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about changes in heterosynaptic plasticity, and associated behavioral consequences, following experimental manipulation of adenosine A1 receptors (A1R). We show that, compared to wild-type controls, A1R-knockout mice have impaired synaptic plasticity in visual cortex neurons, coupled with significant deficits in visual discrimination learning. Deficits in A1R-knockouts were seen specifically during re-learning, becoming progressively more apparent with learning on sequential visual discrimination tasks of increasing complexity. These behavioral results confirm our model predictions, and provide the first experimental evidence for a proposed role of heterosynaptic plasticity in learning.

Neuronal Adenosine A1 Receptor is Critical for Olfactory Function but Unable to Attenuate Olfactory Dysfunction in Neuroinflammation

“…The odor TMT has been used in several studies and the circuits activated by this odor are well understood ( Kobayakawa et al, 2007 ; Saito et al, 2017 ; Sakano, 2020 ). We also excluded confounding changes in anxiety and curiosity in the neuron-specific A 1 R-deficient mice that confirmed previous results using global A 1 R-deficient mice ( Chasse et al, 2021 ), whereas other studies have reported increased anxiety in A 1 R-deficient mice ( Johansson et al, 2001 ; Giménez-Llort et al, 2002 ).…”

“…The odor TMT has been used in several studies and the circuits activated by this odor are well understood (Kobayakawa et al, 2007;Saito et al, 2017;Sakano, 2020). We also excluded confounding changes in anxiety and curiosity in the neuron-specific A 1 R-deficient mice that confirmed previous results using global A 1 R-deficient mice (Chasse et al, 2021), whereas other studies have reported increased anxiety in A 1 Rdeficient mice (Johansson et al, 2001;Giménez-Llort et al, 2002). On the cellular level, immunostainings showed a reduced number of glutamatergic synapses in the external plexiform layer, and recordings of spontaneous PSCs in granule cells revealed a lower input frequency in the A 1 R flx/flx ;SNAP25 Cre mice.…”

Enhanced Non-Associative Long-Term Potentiation in Immature Granule Cells in the Dentate Gyrus of Adult Rats

“…Computational studies predicted the role of heterosynaptic plasticity in learning on sequential tasks. Evidence in support of this prediction for organism-level learning was provided in a recent work demonstrating that impairment of heterosynaptic plasticity in adenosine A1 receptor knockout mice is accompanied by a selective impairment of re-learning on consequent tasks but no impairment in the initial learning (Chasse et al, 2021 ). Results of the present study propose an additional role, which non-associative heterosynaptic plasticity could play at GABA-ergic synapses during maturation of newborn granule cells in the adult dentate gyrus.…”

“…Three trains (one per minute) of 10 bursts (at 1 Hz) of depolarizing pulses were applied. Prior research showed that intracellular tetanization can induce bidirectional plasticity (LTP or LTD) in excitatory and inhibitory neurons in the visual cortex (Volgushev et al, 2000 , 2016 ; Bannon et al, 2017 ; Chistiakova et al, 2019 ; Chasse et al, 2021 ), in the auditory cortex (Lee et al, 2012 ), and in the hippocampus (Kuhnt et al, 1994 ). Similar protocols, consisting of postsynaptic spikes without presynaptic activation, can induce plasticity of inhibitory transmission in visual (Kurotani et al, 2003 , 2008 ) and somatosensory (Lourenço et al, 2014 ) cortex.…”

“…Of note is also that net potentiation in immature neurons was due to a more frequent occurrence of LTP, while the magnitude of LTP in potentiated inputs was not different in immature and mature cells. This indicates that underlying mechanism might be a developmental change of the triggering or/and thresholds for induction of LTP and LTD, such as a shift in the balance between R-type calcium channels that mediate potentiation and L-type channels that mediate depression of GABA-ergic transmission in L5 pyramidal cells (Kurotani et al, 2008 ), or expression of other receptors regulating LTP/LTD balance of heterosynaptic changes, such as adenosine A1 receptors at excitatory synapses onto cortical neurons (Bannon et al, 2017 ; Chasse et al, 2021 ).…”