Dataset Information

Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice.

ABSTRACT: Auxilin (DNAJC6/PARK19), an endocytic co-chaperone, is essential for maintaining homeostasis in the readily releasable pool (RRP) by aiding clathrin-mediated uncoating of synaptic vesicles. Its loss-of-function mutations, observed in familial Parkinson's disease (PD), lead to basal ganglia motor deficits and cortical dysfunction. We discovered that auxilin-knockout (Aux-KO) mice exhibited impaired pre-synaptic plasticity in layer 4 to layer 2/3 pyramidal cell synapses in the primary visual cortex (V1), including reduced short-term facilitation and depression. Computational modeling revealed increased RRP refilling during short repetitive stimulation, which diminished during prolonged stimulation. Silicon probe recordings in V1 of Aux-KO mice demonstrated disrupted visual cortical circuit responses, including reduced orientation selectivity, compromised visual mismatch negativity, and shorter visual familiarity-evoked theta oscillations. Pupillometry analysis revealed an impaired optokinetic response. Auxilin-dependent pre-synaptic endocytosis dysfunction was associated with deficits in pre-synaptic plasticity, visual cortical functions, and eye movement prodromally or at the early stage of motor symptoms.

SUBMITTER: Cheng X

PROVIDER: S-EPMC10520332 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice.

Cheng Xi X Tang Yu Y Vidyadhara D J DJ Li Ben-Zheng BZ Zimmerman Michael M Pak Alexandr A Nareddula Sanghamitra S Edens Paige Alyssa PA Chandra Sreeganga S SS Chubykin Alexander A AA

iScience 20230906 10

Auxilin (DNAJC6/PARK19), an endocytic co-chaperone, is essential for maintaining homeostasis in the readily releasable pool (RRP) by aiding clathrin-mediated uncoating of synaptic vesicles. Its loss-of-function mutations, observed in familial Parkinson's disease (PD), lead to basal ganglia motor deficits and cortical dysfunction. We discovered that auxilin-knockout (Aux-KO) mice exhibited impaired pre-synaptic plasticity in layer 4 to layer 2/3 pyramidal cell synapses in the primary visual corte ...[more]

PMID: 37766983

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Project description:Rett syndrome (RTT) is a neurodevelopment disorder associated with intellectual disabilities and caused by loss-of-function mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes in cortical excitability occur in RTT individuals and Mecp2-deficient mice, including hippocampal network hyperactivity and higher frequency of spontaneous multiunit spikes in the CA3 cell body layer. Here, we describe impaired synaptic inhibition and an excitation/inhibition (E/I) imbalance in area CA3 of acute slices from symptomatic Mecp2 knockout male mice (referred to as Mecp2(-/y) ). The amplitude of TTX-resistant miniature inhibitory postsynaptic currents (mIPSC) was smaller in CA3 pyramidal neurons of Mecp2(-/y) slices than in wildtype controls, while the amplitude of miniature excitatory postsynaptic currents (mEPSC) was significantly larger in Mecp2(-/y) neurons. Consistently, quantitative confocal immunohistochemistry revealed significantly lower intensity of the alpha-1 subunit of GABAA Rs in the CA3 cell body layer of Mecp2(-/y) mice, while GluA1 puncta intensities were significantly higher in the CA3 dendritic layers of Mecp2(-/y) mice. In addition, the input/output (I/O) relationship of evoked IPSCs had a shallower slope in CA3 pyramidal neurons Mecp2(-/y) neurons. Consistent with the absence of neuronal degeneration in RTT and MeCP2-based mouse models, the density of parvalbumin- and somatostatin-expressing interneurons in area CA3 was not affected in Mecp2(-/y) mice. Furthermore, the intrinsic membrane properties of several interneuron subtypes in area CA3 were not affected by Mecp2 loss. However, mEPSCs are smaller and less frequent in CA3 fast-spiking basket cells of Mecp2(-/y) mice, suggesting an impaired glutamatergic drive in this interneuron population. These results demonstrate that a loss-of-function mutation in Mecp2 causes impaired E/I balance onto CA3 pyramidal neurons, leading to a hyperactive hippocampal network, likely contributing to limbic seizures in Mecp2(-/y) mice and RTT individuals.

Dataset Information

Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice.

Publications

Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice.

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