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Review
. 2013 Feb 18:7:17.
doi: 10.3389/fncir.2013.00017. eCollection 2013.

Structural plasticity in the dentate gyrus- revisiting a classic injury model

Julia V Perederiy  1 , Gary L Westbrook
Affiliations
Review

Structural plasticity in the dentate gyrus- revisiting a classic injury model

Julia V Perederiy et al. Front Neural Circuits. .

Abstract

The adult brain is in a continuous state of remodeling. This is nowhere more true than in the dentate gyrus, where competing forces such as neurodegeneration and neurogenesis dynamically modify neuronal connectivity, and can occur simultaneously. This plasticity of the adult nervous system is particularly important in the context of traumatic brain injury or deafferentation. In this review, we summarize a classic injury model, lesioning of the perforant path, which removes the main extrahippocampal input to the dentate gyrus. Early studies revealed that in response to deafferentation, axons of remaining fiber systems and dendrites of mature granule cells undergo lamina-specific changes, providing one of the first examples of structural plasticity in the adult brain. Given the increasing role of adult-generated new neurons in the function of the dentate gyrus, we also compare the response of newborn and mature granule cells following lesioning of the perforant path. These studies provide insights not only to plasticity in the dentate gyrus, but also to the response of neural circuits to brain injury.

Keywords: adult neurogenesis; dentate gyrus; perforant path lesion; reactive synaptogenesis.

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Figures

Figure 1
Figure 1
Plasticity in the central nervous system. (A) Axons from two different pathways synapse onto spines on the same dendrites. Each synapse is surrounded by astrocytes (red), microglia (green), and extracellular matrix. (B) Increases in activity, such as occur during learning, can strengthen connections by axonal sprouting (blue) as well as formation of new filopodia and dendritic spines (*). Adjacent afferents, surrounding glia, and extracellular matrix are relatively unaffected. (C) Disruption of afferents, such as following injury, leads to degeneration of damaged axons (dotted lines), activation of astrocytes, microglia, and extracellular matrix, as well as retraction of dendritic spines (*). Compensatory sprouting of undamaged afferents from another brain region (orange) can form new synapses, including contacts with denervated spines (#).
Figure 2
Figure 2
Adaptive and maladaptive glial changes following injury. The degree of astrogliosis depends on the severity of injury. (A) Glia and extracellular matrix at baseline. Astrocytes are tiled, i.e., their processes do not overlap with neighboring astrocytes. Microglia are interspersed throughout the region. (B) Mild injury triggers activation of microglia and astrocytes. Astrocytes and microglia increase in size and acquire more complex process morphology, but astrocytes maintain their tiled formation. This response is considered adaptive because it limits the spread of degeneration away from the site of injury, dampens excitotoxicity, and promotes tissue regeneration. Such glial activation typically resolves within a few weeks after a mild, transient injury. (C) In contrast severe injury causes reactive astrocytes to invade neighboring domains, recruit reactive microglia, and increases secretion of extracellular molecules. This results in formation of a persistent glial scar that can be impenetrable to sprouting axons.
Figure 3
Figure 3
Lamina-specific axon sprouting and reactive gliosis following perforant path lesion. The molecular layer of the adult dentate gyrus is a highly laminated structure with afferent inputs segregated based on their origin and neurotransmitter phenotype. All afferent axons form either symmetrical or asymmetrical synapses with mature granule cells (black traces) in a lamina-specific manner. Left panel: the inner molecular layer (IML) is occupied by the glutamatergic commissural/associational fibers (C/A) that arise from mossy cells in the ipsi- or contralateral hilus. The middle and outer molecular layer (MML, OML) are occupied predominantly by the glutamatergic perforant path (MPP, LPP), which originates in the ipsilateral entorhinal cortex. In rats (but not in mice), there is also a crossed glutamatergic projection from the contralateral entorhinal cortex (cEC) that terminates in the outermost molecular layer (OML). Cholinergic axons (ACh) from the septal nuclei/diagonal band of Broca are interspersed throughout the molecular layer, as are astrocytes (red) and quiescent microglia (green). Right panel: lesion of the entorhinal cortex (red X, left panel) transects both medial and lateral perforant path, thus eliminating the majority of excitatory input into the dentate gyrus. Degeneration of these axons induces lamina-specific sprouting of the remaining septohippocampal (ACh), commissural/associational (C/A), and crossed entorhino-dentate (cEC) afferents. In the rat, the contralateral entorhino-dentate projection (cEC) partially restores excitatory innervation of the mature granule cells (black trace), however, their dendritic length and complexity are still reduced. The microglia (green) and astrocytes (red) become “activated” following lesion, but this response is limited to the deafferented zone. Note the expansion of the inner molecular layer and shrinkage of the outer layers.
Figure 4
Figure 4
Structural plasticity following perforant path lesions. Left panels (modified from Steward and Messenheimer, 1978): Mature cat hippocampus histochemically stained for acetyl cholinesterase (AChE) activity at 60 days post-lesion. The density of AChE is dramatically increased in the denervated outer molecular layer (A,B, top right, dark band), consistent with sprouting of the cholinergic septohippocampal axons following lesion. Also note that the thickness of the inner molecular layer is increased due to sprouting of the glutamatergic commissural/associational fibers (C,D, bottom right, double arrows). Right panels (modified from Matthews et al., 1976b): Ultrastructural evidence for synaptic regeneration in the denervated zone at 60 days post-lesion in the mature rat. Serial sections through a complex spine (a,b,c,d, green) show synaptic contacts with a degenerating bouton “D” as well as with a regenerating axon “*.” a = spine apparatus.
Figure 5
Figure 5
Adult neurogenesis and synaptic integration following perforant path lesion. Data montage of dorsal hippocampus in mature mouse. Left panel: The morphology of 14-day-old newborn granule cells (POMC-EGFP, green), and typical maturation of newborn granule cells (white traces) shown at 14- (white cell at right in panel) and 21- (white cell at left in panel) days post-mitosis. At 14 days, dendritic arbors are limited to the inner molecular layer (IML) and lack spines, whereas dendrites of 21-day-old granule penetrate the middle (MML) and outer (OML) molecular layers and develop spines. Typical dendritic spine densities are shown at far left for the inner (IML) and outer (OML) molecular layers. Right panel: Unilateral perforant path lesion increases proliferation of newborn granule cells (POMC-EGFP, 14 days post-mitosis) and reduces their dendritic outgrowth (white traces). Traces of 14- (left trace) and 21- (right trace) day-old granule cells shown at 14- (left) and 21- (right) days post-lesion, respectively. Dendritic length and complexity are reduced relative to those of newborn granule cells in the contralateral hemisphere (left panel). At 21 days post-lesion de novo spine formation in 21-day old granule cells (far right panels) is decreased in the deafferented zone (OML), but increased in the intact inner molecular layer (IML). Note the dramatically reduced staining for a marker for glutamatergic axons (vGlut1, red) at 21 days post-lesion in the middle and outer molecular layers illustrating the absence of excitatory inputs in the denervated zone.
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