Structural plasticity of dendritic spines.

Dendritic spines are small mushroom-like protrusions arising from neurons where most excitatory synapses reside. Their peculiar shape suggests that spines can serve as an autonomous postsynaptic compartment that isolates chemical and electrical signaling. How neuronal activity modifies the morphology of the spine and how these modifications affect synaptic transmission and plasticity are intriguing issues. Indeed, the induction of long-term potentiation (LTP) or depression (LTD) is associated with the enlargement or shrinkage of the spine, respectively. This structural plasticity is mainly controlled by actin filaments, the principal cytoskeletal component of the spine. Here we review the pioneering microscopic studies examining the structural plasticity of spines and propose how changes in actin treadmilling might regulate spine morphology.

Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra.

Spontaneous spreading depolarizations (SDs) occur in the penumbra surrounding ischemic core. These SDs, often referred to as peri-infarct depolarizations, cause vasoconstriction and recruitment of the penumbra into the ischemic core in the critical first hours after focal ischemic stroke; however, the real-time spatiotemporal dynamics of SD-induced injury to synaptic circuitry in the penumbra remain unknown. A modified cortical photothrombosis model was used to produce a square-shaped lesion surrounding a penumbra-like "area at risk" in middle cerebral artery territory of mouse somatosensory cortex. Lesioning resulted in recurrent spontaneous SDs. In vivo two-photon microscopy of green fluorescent protein-expressing neurons in this penumbra-like area at risk revealed that SDs were temporally correlated with rapid (<6 s) dendritic beading. Dendrites quickly (<3 min) recovered between SDs to near-control morphology until the occurrence of SD-induced terminal dendritic injury, signifying acute synaptic damage. SDs are characterized by a breakdown of ion homeostasis that can be recovered by ion pumps if the energy supply is adequate. Indeed, the likelihood of rapid dendritic recovery between SDs was correlated with the presence of nearby flowing blood vessels, but the presence of such vessels was not always sufficient for rapid dendritic recovery, suggesting that energy needs for recovery exceeded energy supply of compromised blood flow. We propose that metabolic stress resulting from recurring SDs facilitates acute injury at the level of dendrites and dendritic spines in metabolically compromised tissue, expediting penumbral recruitment into the ischemic core.

Persistent working memory dysfunction following traumatic brain injury: evidence for a time-dependent mechanism.

The prefrontal cortex is highly vulnerable to traumatic brain injury (TBI) resulting in the dysfunction of many high-level cognitive and executive functions such as planning, information processing speed, language, memory, attention, and perception. All of these processes require some degree of working memory. Interestingly, in many cases, post-injury working memory deficits can arise in the absence of overt damage to the prefrontal cortex. Recently, excess GABA-mediated inhibition of prefrontal neuronal activity has been identified as a contributor to working memory dysfunction within the first month following cortical impact injury of rats. However, it has not been examined if these working memory deficits persist, and if so, whether they remain amenable to treatment by GABA antagonism. Our findings show that working memory dysfunction, assessed using both the delay match-to-place and delayed alternation T-maze tasks, following lateral cortical impact injury persists for at least 16 weeks post-injury. These deficits were found to be no longer the direct result of excess GABA-mediated inhibition of medial prefrontal cortex neuronal activity. Golgi staining of prelimbic pyramidal neurons revealed that TBI causes a significant shortening of layers V/VI basal dendrite arbors by 4 months post-injury, as well as an increase in the density of both basal and apical spines in these neurons. These changes were not observed in animals 14 days post-injury, a time point at which administration of GABA receptor antagonists improves working memory function. Taken together, the present findings, along with previously published reports, suggest that temporal considerations must be taken into account when designing mechanism-based therapies to improve working memory function in TBI patients.

Preliminary morphological evidence that vertebral hypomobility induces synaptic plasticity in the spinal cord.

OBJECTIVE: A widely accepted theoretical model suggests that vertebral hypomobility can cause pain and abnormal spinal mechanics because of changes in sensory input from spinal and paraspinal tissues. The purpose of this pilot study was 3-fold: (1) to make a preliminary determination if chronic vertebral hypomobility at L4 through L6 in the rat would affect synaptic density and/or morphology in the superficial dorsal horn of the L2 spinal cord level, (2) to identify relevant outcome variables for future studies, and (3) to obtain preliminary data that would permit estimating an appropriate sample size for future studies. METHODS: Using an established rat model, we fixed 3 contiguous lumbar segments (L4-L6) for 8 weeks with a specially engineered vertebral fixation device. Electron micrographs were obtained from 2 animals from the experimental (fixed) group and each of 3 control groups (no surgery, surgery but no devices implanted, and devices implanted but not fixed). Synapses were randomly selected using a stereological approach and were analyzed for symmetry, curvature, type of postsynaptic profile, and perforations. The synaptic density was also estimated. RESULTS: There was increased synaptic density and percentage of positively curved synapses in the dorsal horn of experimental animals as compared with controls. Experimental animals had a lower percentage of axospinous synapses, with a concomitant increase in the percentage of synapses on dendritic shafts. CONCLUSIONS: These preliminary data suggest for the first time that chronic vertebral hypomobility at L4 through L6 in the rat affects synaptic density and morphology in the superficial dorsal horn of the L2 spinal cord level. More definitive studies are warranted, and the biologic significance of these finding should be investigated.

Double dissociation between long-term depression and dendritic spine morphology in cerebellar Purkinje cells.

Experiments in hippocampal area CA1 suggest that long-term potentiation could be associated with spine addition and enlargement, and long-term depression (LTD) with spine shrinkage and loss. Is this a general principle of synaptic plasticity? We used two-photon microscopy to measure dendritic spines in rat cerebellar Purkinje cells. Neither local synaptic induction of LTD nor global chemical induction of LTD changed spine number or size. Conversely, a manipulation that evoked persistent dendritic spine retraction did not alter parallel fiber-evoked excitatory postsynaptic currents.

NOS-positive local circuit neurons are exclusively axo-dendritic cells both in the neo- and archi-cortex of the rat brain.

Neuronal nitric oxide synthase (nNOS)-containing neurons and axon terminals were examined in the rat somatosensory and temporal neocortex, in the CA3/a-c areas of Ammon's horn and in the hippocampal dentate gyrus. In these areas, only nonpyramidal neurons were labeled with the antibody against nNOS. Previous observations suggested that all nNOS-positive nonpyramidal cells are GABAergic local circuit neurons, which form exclusively symmetric synapses. In agreement with this, nNOS-positive axon terminals in the hippocampal formation formed symmetric synapses exclusively with dendritic shafts. In the neocortex, in contrast, in addition to the nNOS-positive axon terminals that formed synapses with unlabeled spiny and aspiny dendrites and with nNOS-positive aspiny dendrites, a small proportion of the nNOS-positive axon terminals formed symmetric synapses with dendritic spines. These results suggest that nNOS-positive local circuit neurons form a distinct group of axo-dendritic cells displaying slightly different domain specificity in the archi- and neocortex. However, nNOS-positive cells show no target selectivity, because they innervate principal cells and local circuit neurons. Afferents to the NOS-positive cells display neither domain nor target selectivity, because small unlabeled terminals formed synapses with both the soma or dendrites of nNOS-positive neurons and an adjacent unlabeled dendrite or spine in both the hippocampal formation and in neocortex.