Biology subjects

Kind, P. C.

Publications and source records attributed to Kind, P. C..

22 records · Page 2Linked to original sources

bioRxiv2020

FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

Synaptic vesicle (SV) recycling defects are linked to neurodevelopmental disorders, including fragile X syndrome (FXS), which results from loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. Hyperexcitability of neuronal circuits is a key feature of FXS, therefore we investigated whether SV recycling was affected by the absence of FMRP during increased neuronal activity. We revealed that primary neuronal cultures from a Fmr1 knockout rat model display a specific defect in activity-dependent bulk endocytosis (ADBE). This defect resulted in an inability of Fmr1 knockout neurons to sustain SV recycling during high frequency stimulation. Using a molecular replacement strategy, we also revealed that a human FMRP mutant that cannot bind BK channels failed to correct ADBE dysfunction in knockout neurons, however this dysfunction was corrected by BK channel agonists. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of ADBE, suggesting intervention via this endocytosis mode may correct hyperexcitabiltiy observed in FXS. SUMMARYFragile X syndrome (FXS) is caused by loss of fragile X mental retardation protein (FMRP). Bonnycastle et al show that FMRP is specifically required for activity-dependent bulk endocytosis (ADBE), revealing 1) FMRP sustains neurotransmitter release and 2) intervention via ADBE may correct circuit hyperexcitabilty in FXS.

neuroscience↗

bioRxiv2020

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3-/y rat model of autism

Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. Whilst examining fear in a rat model of ASD/ID lacking Nlgn3, we observed that they display a greater propensity to exhibit flight responses in contrast to classic freezing seen in wildtypes during fearful situations. Consequently, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. In ex vivo slices from Nlgn3-/y, rats, dorsal PAG (dPAG) neurons showed intrinsic hyperexcitability. Further analysis of this revealed lower magnitude in vivo dPAG stimulation evoked flight behaviour in Nlgn3-/y, rats, indicating the functional impact of the increased cellular excitability. This study provides new insight into potential pathophysiologies leading to emotional disorders in individuals with ASD.

neuroscience↗

bioRxiv2019

A sex difference in the composition of the rodent postsynaptic density

SynGAP is a postsynaptic density (PSD) protein that binds to PDZ domains of the scaffold protein PSD-95. We previously reported that heterozygous deletion of synGAP in mice is correlated with increased steady-state levels of other key PSD proteins that bind PSD-95, although the level of PSD-95 remains constant (Walkup et al., 2016). For example, the ratio to PSD-95 of Transmembrane AMPA-Receptor-associated Proteins (TARPs), which mediate binding of AMPA-type glutamate receptors to PSD-95, was increased in young synGAP+/- mice. Here we show that a highly significant increase in TARP in the PSDs of young synGAP+/- rodents is present only in females and not in males. The data reveal a sex difference in the adaptation of the PSD scaffold to synGAP heterozygosity.

neuroscience↗

bioRxiv2018

Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome

Cellular and circuit hyperexcitability are core features of Fragile X Syndrome and related autism spectrum disorder models. However, a synaptic basis for this hyperexcitability has proved elusive. We show in a mouse model of Fragile X Syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, near-simultaneous uncaging at multiple spines revealed fewer spines are required to trigger an action potential. This arose, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents. Super-resolution microscopy revealed no change in dendritic spine morphology, pointing to an absence of a structure-function relationship. However, ultrastructural analysis revealed a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine excitatory currents following glutamate uncaging. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.

neuroscience↗