Abstract
AMPA receptors (AMPARs) mediate excitatory neurotransmission in the central nervous system (CNS) and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1-GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here, we demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ~80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational network modeling incorporating these changes revealed that deletion of GluA4 impairs granule cell expansion coding, which is important for pattern separation and associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.
Highlights
AMPA receptors (AMPARs) are essential for excitatory neurotransmission in the central nervous system (CNS)
Our findings demonstrate the importance of the GluA4 AMPAR subunit for cerebellar input layer synaptic function and associative memory formation
GluA4-KO granule cells (GCs) had a smaller root-meansquare noise of the baseline holding current and smaller bicuculline-sensitive conductance compared with WT (39.0 ± 9.6 pS/pF vs. 83.0 ± 13.3 pS/pF, p = 0.022; Figure 2E–F). These findings show that tonic GABAAR-mediated inhibition is reduced in GluA4-KO GCs, in line with the lack of effect of bicuculline on the input-output relationship in these animals
Summary
AMPA receptors (AMPARs) are essential for excitatory neurotransmission in the central nervous system (CNS). Despite compensatory changes in tonic inhibition and NMDA receptor-mediated synaptic input, the pronounced decrease of AMPAR-mediated excitation caused a severe deficit in synaptic integration during high-frequency transmission. These synaptic changes impaired pattern separation and learning performance of a feedforward network model. Our findings demonstrate the importance of the GluA4 AMPAR subunit for cerebellar input layer synaptic function and associative memory formation
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