Microglia: Mediators of experience-driven corrective neuroplasticity

Abstract

Neural connectivity is essential for brain function: this is initially established via early axon guidance mechanisms and subsequently refined by synaptic pruning. Alterations in the patterns of neural connectivity, arising due to changes in either of these processes, are found in neurodevelopmental conditions. Microglia, the brain's resident immune cell, are recognised mediators of synaptic pruning. Unlike axon guidance, synaptic pruning occurs over protracted periods of postnatal life and can be profoundly impacted by experience. Little is known about whether targeted microglial synaptic pruning could be recruited to compensate for alterations in neural connectivity arising due to deleterious changes in other neurodevelopmental processes, such as axon guidance. Here we review our recent work which has addressed this by examining the effect of Environmental Enrichment (EE) on the miswired visual circuitry of mice lacking the axon guidance molecule Ten-m3. Notably, exposure to EE commenced around birth (but not from weaning or later) triggered selective removal of miswired retinal inputs in the visual thalamus of these Ten-m3 knockout mice. Most importantly, our work identifies selective microglial engulfment of neural connections during a defined postnatal window, as a likely mediator of this effect of early EE. The findings reviewed here emphasise the importance of early life experience in shaping neural circuitry, particularly when early development has been compromised by genetic factors. They also provide a potential mechanistic underpinning for the results of recent clinical trials investigating the effectiveness of early, experience-based interventions for human neurodevelopmental conditions.

Keywords: Environmental enrichment; Experience; Microglia; Neurodevelopment; Neurodevelopmental condition; Plasticity; Ten-m3; Visual System.

Fig. 1

Schematic overview and breakdown of the broad organisation of the vision forming pathway in mice. A, In-situ schematic overview detailing the location of the retina (yellow), superior colliculus (SC - pink) and V1 (Green) in mice. At the midline, a large portion of RGCs decussate in the optic chiasm (OC – thick black cross in A) to form the contralateral RGC projection. The remainder form the ipsilateral RGC projection. RGC axons then pass through the optic tract (OT). Most RGC axons project to the SC, with a portion also sending collateral projections to the dLGN. B, Schematic overview of visuotopic organisation. The mouse visual field (displayed at top – coloured regions only) goes from roughly 40º below the horizontal, up to around 80º elevation and 120^º laterality. The binocular visual field (pink and yellow regions) is relatively small and very dorsally orientated. The visual receptivity of the retina, dLGN and V1 is colour coded with respect to the visual field schematic (top). the small black stars in 4 of the 6 coronal sections, are an example of a visuotopically corresponding projection line in series coronal sections - dLGN loci all receptive to the same point in visual space (see Ai – top, for rough point). C, schematic overview of eye specific projection patterns. Ipsilateral RGCs (left - dark yellow; right - dark blue) arise from a small, ventral temporal portion of the retina. Contralateral RGCs (light yellow - left, light blue - right) arise from the entire retina. In the dLGN, ipsilateral RGCs synapse in a small dorsal-medially located patch (dark yellow - left; dark blue -right), largely segregated from contralateral RGC inputs (light blue - left; light yellow - right). in V1, relayed ipsilateral retinal input from the dLGN synapses in a lateral segment (‘checked’ dark yellow – left V1; ‘checked’ dark blue – right V1) where it intermingles with visually corresponding contralateral retinal input. Grey dotted line (B, C) indicates midline. Retinal ganglion cell (RGC); dorsal lateral geniculate nucleus (dLGN); primary visual cortex (V1); SC (superior colliculus); VTC (ventral temporal crescent); ON (optic nerve); OT (optic tract); optic chiasm (OC); dorsal (D); ventral (V); nasal (N); temporal (T); lateral (L); medial (M); rostral (R); caudal (C). *schematic - not to scale*. See main text for literature references.

Fig. 2

Ipsilateral RGC axons in Ten-m3 KO mice exit the optic tract early during early development such that they terminate in the adult dLGN in a significantly ventral-laterally elongated region, that is not visuo-topically aligned with contralateral RGC terminals. A, in both WT and Ten-m3 KO mice, ipsilateral RGC axons (overlayed over schematic dLGN sections in brown) grow ventral to dorsal in the optic tract along the dorsolateral dLGN border, exiting the optic tract between embryonic day (E)18 and birth (P0). in Ten-m3 KO mice though, a portion of these ipsilateral RGC axons exit the optic tract early to terminate significantly more ventral-laterally in the dLGN (black arrow), than they do in WT mice. The monocular segregation of ipsilateral (dark yellow) and contralateral (light blue) retinogeniculate terminal zones, still occurs normally in Ten-m3 KO mice. B, schematic comparing eye specific retinogeniculate projection patterns in the dLGN of Ten-m3 KO and WT mice - rather than synapsing in a dorsal-medially confined ‘patch’ (WT mouse patterning), ipsilateral retinogeniculate terminals in Ten-m3 KO mice synapse significantly more ventral-laterally (black arrow) and a little more dorsal-medially. C, schematic comparing visuotopy in the dLGN of Ten-m3 KO and WT mice. The visual receptivity of the retina and dLGN is colour coded - the binocular portion of the visual field (region seen by both eyes) is in pink (left visual field) and yellow (right visual field) and the monocular portions of the visual field, in blue (left visual field) and Green (right visual field). The altered innervation pattern of ipsilateral RGCs in the Ten-m3 KO mice (outlined in B), disturbs the visuotopic alignment of ipsilateral and contralateral inputs (black arrow) that is usually found in the dLGN of wildtype mice. A-C, schematic of mid-rostral, sections of dLGN are presented. Ventral-temporal crescent (VTC); Knock-out (KO); dorsal lateral geniculate nucleus (dLGN); dorsal (D); ventral (V); lateral (L); medial (M). *schematic - not to scale*. See main text for literature references.

Fig. 3

Environmental enrichment from birth in Ten-m3 KO mice triggers focal pruning of their most visuo-topically mis-mapped ipsilateral retinogeniculate terminals, in a defined postnatal window. A, in wild-type mice, EE from birth until P7 or P26–27 does not change the area occupied by ipsilateral retinogeniculate terminals (dark yellow; the area where contralateral retinogeniculate terminals occupy is in light blue). EE from birth until P43–44 does trigger generalised pruning of ipsilateral retinogeniculate terminals though (I.e., not focal; delineated by black dotted line). B, in Ten-m3 KO mice, EE from birth until P7 or P18 also does not alter the area occupied by ipsilateral retinogeniculate terminals (dark yellow). EE from birth until P26–27 or P42–44, however, triggers very focal pruning (delineated with arrow and black dotted line) of their most visuotopically mis-mapped ipsilateral retinogeniculate terminals (I.e., those most ventral-laterally located in the dLGN). this EE-trigger pruning in Ten-m3 KO mice is more pronounced at P42–44 than at P26–27, suggesting it is actively underway at P26–27. Schematic of mid-rostral sections of dLGN are presented. Knock-out (KO); dorsal lateral geniculate nucleus (dLGN); dorsal (D); ventral (V); lateral (L); medial (M); postnatal day (P). see main text for literature references.