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.
Developmental dyslexia is a common neurodevelopmental disorder characterized by difficulties in reading and writing. Although underlying biological and genetic mechanisms remain unclear, anomalies in phonological processing and auditory processing have been associated with dyslexia. Several candidate risk genes have also been identified, with KIAA0319 as a main candidate. Animal models targeting the rodent homolog (Kiaa0319) have been used to explore putative behavioral and anatomic anomalies, with mixed results. For example after downregulation of Kiaa0319 expression in rats via shRNA, significant adult rapid auditory processing impairments were reported, along with cortical anomalies reflecting atypical neuronal migration. Conversely, Kiaa0319 knockout (KO) mice were reported to have typical adult auditory processing, and no visible cortical anomalies. To address these inconsistencies, we tested Kiaa0319 KO mice on auditory processing tasks similar to those used previously in rat shRNA knockdown studies. Subsequent neuroanatomic analyses on these same mice targeted medial geniculate nucleus (MGN), a receptive communication‐related brain structure. Results confirm that Kiaa0319 KO mice exhibit significant auditory processing impairments specific to rapid/brief stimuli, and also show significant volumetric reductions and a shift toward fewer large and smaller neurons in the MGN. The latter finding is consistent with post mortem MGN data from human dyslexic brains. Combined evidence supports a role for KIAA0319 in the development of auditory CNS pathways subserving rapid auditory processing functions critical to the development of speech processing, language, and ultimately reading. Results affirm KIAA0319 variation as a possible risk factor for dyslexia specifically via anomalies in central acoustic processing pathways.
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.HighlightsSynaptic plasticity is impaired in visual cortex neurons in adenosine A1R knockout miceHomosynaptic and heterosynaptic plasticity in A1R KO mice is dominated by depressionLearning on sequential, increasingly complex visual tasks is impaired in A1R KO miceLearning deficits match predicted effects of impaired heterosynaptic plasticity
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