Biology subjects

Baxter, P. S.

Publications and source records attributed to Baxter, P. S..

3 recordsLinked to original sources

bioRxiv2026

Mononuclear myeloid cells mount an adaptive protective response to intracerebral haemorrhage by activation of NRF2

Following intracerebral haemorrhage (ICH), secondary injury contributes to negative outcomes. Here, we describe inter-dependent injurious and adaptive-protective pathways that form a therapeutically modifiable ICH response. In perihaematomal tissue from post-mortem ICH patients, transcriptomic analysis pointed to concurrent perihaematomal activation of the cytoprotective stress-induced transcription factor NRF2 and activation of interferon responses, with mononuclear myeloid cells (microglia and monocyte-derived cells, MMCs) and astrocytes contributing to this signature. In vitro, microglia-astrocyte-neuron co-culture studies revealed that microglial NRF2 activation was induced by clot-conditioned medium and could influence the interferon pathway in both microglia themselves as well as astrocytes. In vivo, MMC-specific deletion of NRF2 inhibited NRF2 target-gene induction, exacerbated interferon pathway activation following ICH, and impaired functional recovery. Pharmacological NRF2 activation suppressed interferon pathway induction post-ICH, and direct interferon pathway antagonism rescued neurological recovery deficits caused by MMC-specific NRF2 deficiency. Thus, augmenting NRF2- or inhibiting interferon-signalling may improve outcomes after ICH.

neuroscience↗

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↗

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↗