Biology subjects

Wyllie, D. J.

Publications and source records attributed to Wyllie, D. J..

5 recordsLinked to original sources

bioRxiv2026

Astrocytes transform the transcriptomic and epigenetic landscape of developing cortical neurons to promote activity via intrinsic excitability control

Astrocytes are implicated in neuronal development and function, particularly of synapses, but their genome-wide impact is unclear. We show that cortical astrocytes trigger epigenetic remodelling in developing cortical neurons and widespread transcriptomic changes distinct from neurons intrinsic developmental trajectory. These changes can cause an emergence of neuronal firing activity independent of functional excitatory synaptogenesis. The mechanism is via through astrocyte-derived signals causing the transcriptional repression of inwardly-rectifying K+-channels (Kirs), causing a pro-excitatory shift in intrinsic properties. This places neurons in a zone of excitability whereupon cell-autonomous homeostatic control was activated, also associated with Kir regulation. Astrocyte-induced neuronal genes were enriched for schizophrenia, epilepsy, ADHD and Alzheimers disease risk, disorders associated with circuit imbalance. Thus, astrocyte-to-neuron signaling can alter firing via intrinsic properties in addition to the classical synaptogenic mechanism. The opposing actions of astrocytes and neuronal activity in regulating neuronal intrinsic properties may prevent hyper- or hypo-activity in neuronal circuits

neuroscience↗

bioRxiv2024

Typical development of synaptic and neuronal properties can proceed without microglia

Brain-resident macrophages, microglia, have been proposed to play an active role in synaptic refinement and maturation, influencing plasticity and circuit-level connectivity. Here we show that a variety of neurodevelopmental processes previously attributed to microglia can proceed without them. Using a genetically modified mouse which lacks microglia (Csf1r{Delta}FIRE/{Delta}FIRE) we find that intrinsic properties, synapse number and synaptic maturation are largely normal in the hippocampal CA1 region and somatosensory cortex at stages where microglia have been implicated. Seizure susceptibility and hippocampal-prefrontal cortex coherence in awake behaving animals, processes disrupted in mice deficient in microglia-enriched genes, are also normal. Similarly, eye-specific segregation of inputs into the lateral geniculate nucleus proceeds normally in the absence of microglia. Single cell/nucleus transcriptomic analyses of neurons and astrocytes did not uncover any substantial perturbation due to microglial absence. Thus, the brain possesses remarkable adaptability to execute developmental synaptic refinement, maturation and connectivity in the absence of microglia.

neuroscience↗

bioRxiv2022

Enhanced hippocampal LTP but typical NMDA receptor and AMPA receptor function in a novel rat model of CDKL5 deficiency disorder

Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a novel Cdkl5 KO rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function underlie the enhanced LTP we observe in the hippocampus of Cdkl5 KO rats. We tested this hypothesis using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. We show that NMDA receptor function and subunit expression are unaltered throughout development, and Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 KO rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability in Cdkl5 KO rats and supported by typical expression of pre-synaptic proteins in synaptosome preparations. Together these data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits might contribute to the altered plasticity.

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↗

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↗