Simoes de Oliveira, L. | Search bioRxiv

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↗