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Background. The extracellular matrix of the PNS/CNS is unusual in that it is dominated by glycosaminoglycans, especially hyaluronan, whose space filling and hydrating properties make essential contributions to the functional properties of this tissue. Hyaluronan has a relatively simple structure but its space-filling properties ensure micro-compartments are maintained in the brain ultrastructure, ensuring ionic niches and gradients are maintained for optimal cellular function. Hyaluronan has cell-instructive, anti-inflammatory properties and forms macro-molecular aggregates with the lectican CS-proteoglycans, forming dense protective perineuronal net structures that provide neural and synaptic plasticity and support cognitive learning. Aims. To highlight the central nervous system/peripheral nervous system (CNS/PNS) and its diverse extracellular and cell-associated proteoglycans that have cell-instructive properties regulating neural repair processes and functional recovery through interactions with cell adhesive molecules, receptors and neuroregulatory proteins. Despite a general lack of stabilising fibrillar collagenous and elastic structures in the CNS/PNS, a sophisticated dynamic extracellular matrix is nevertheless important in tissue form and function. Conclusions. This review provides examples of the sophistication of the CNS/PNS extracellular matrix, showing how it maintains homeostasis and regulates neural repair and regeneration.

Key Points Matrix metalloproteinases (MMPs) are a large family of mostly secreted, extracellularly acting proteolytic enzymes. In the brain, they have well-described roles in slowly emerging, but long-lasting pathophysiological processes of cell loss and synaptic dysfunction associated with acute injury, ischaemia, neurodegeneration and demyelination. Remodelling of synapse structure and function also underlies normal cognitive processes, such as learning and memory. This Review focuses on recent studies that indicate that MMPs have important roles in driving such synapse plasticity under non-pathological conditions that are distinct from their roles in neuropathophysiology. MMPs are secreted as inactive pro-enzymes (zymogens). Under basal conditions, a large pool of mostly pro-MMPs is situated perisynaptically, poised for activation by plasticity-inducing stimuli, such as long-term potentiation (LTP). Upon induction of LTP, but not other forms of short- or long-lasting plasticity, pro-MMPs are rapidly (within ∼15 min) converted to proteolytically active MMPs through an NMDA receptor-dependent mechanism. Such proteolytically active MMPs then signal through β1-containing integrins to promote dendritic spine enlargement and synaptic potentiation concurrently. Intercellular adhesion molecule 5, which binds to and activates integrins, may be a direct target of perisynaptic MMP proteolysis during LTP. LTP-associated MMP proteolysis is probably then terminated by an increase in the activity of endogenous inhibitors called tissue inhibitors of metalloproteinases. When MMP activity is blocked pharmacologically or genetically, LTP, spine enlargement and behavioural measures of cognitive function are all impaired. Several psychiatric and neurological disorders, including drug addiction, neuropathic pain syndromes and fragile X syndrome, are associated with abnormal or deficient synaptic plasticity. Recent studies indicate that aberrant MMP expression, localization and function may contribute to synaptic plasticity deficits associated with such disorders. A key area for future research is to elucidate how MMP activity transitions from normal, adaptive roles in local synaptic remodelling to deleterious roles that have important pathophysiological cellular and synaptic consequences. This transition probably involves abnormal regulatory mechanisms, leading to excessive, prolonged and widespread MMP activity. Aberrant matrix metalloproteinase (MMP) activity is a well-known contributor to synaptic dysfunction and neuronal loss in CNS injury and disease. In this Review, George W. Huntley discusses how MMPs also make an important contribution to synaptic functional and structural remodelling under nonpathophysiological conditions. Matrix metalloproteinases (MMPs) are extracellularly acting enzymes that have long been known to have deleterious roles in brain injury and disease. In particular, widespread and protracted MMP activity can contribute to neuronal loss and synaptic dysfunction. However, recent studies show that rapid and focal MMP-mediated proteolysis proactively drives synaptic structural and functional remodelling that is crucial for ongoing cognitive processes. Deficits in synaptic remodelling are associated with psychiatric and neurological disorders, and aberrant MMP expression or function may contribute to the molecular mechanisms underlying these deficits. This Review explores the paradigm shift in our understanding of the contribution of MMPs to normal and abnormal synaptic plasticity and function.

Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 ( EHMT1 ) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila , little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome.

In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood. Individual CA1 neurons in MMP-9 −/− mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significantly increases spontaneous neuronal activity in awake MMP-9 −/− mice and enhances response to acute challenge by the excitotoxin kainate. Our data document a novel role for MMP-9-dependent proteolysis: the regulation of several aspects of circuit maturation to constrain excitability throughout life.

We explored whether cerebral cortical impact injury (CCI) effects extend beyond direct lesion sites to affect remote brain networks, and whether acetylcholinesterase (AChE) inhibition elicits discrete changes in functional activation of motor circuits following CCI. Adult male rats underwent unilateral motor-sensory CCI or sham injury. Physostigmine (AChE inhibitor) or saline were administered subcutaneously continuously via implanted minipumps (1.6 micromoles/kg/day) for 3 weeks, followed by cerebral perfusion mapping during treadmill walking using [14C]-iodoantipyrine. Quantitative autoradiographs were analyzed by statistical parametric mapping and functional connectivity (FC) analysis. CCI resulted in functional deficits in the ipsilesional basal ganglia, with increased activation contralesionally. Recruitment was also observed, especially contralesionally, of the red nucleus, superior colliculus, pedunculopontine tegmental nucleus, thalamus (ventrolateral n., central medial n.), cerebellum, and sensory cortex. FC decreased significantly within ipsi- and contralesional motor circuits and between hemispheres, but increased between midline cerebellum and select regions of the basal ganglia within each hemisphere. Physostigmine significantly increased functional brain activation in the cerebellar thalamocortical pathway (midline cerebellum→ventrolateral thalamus→motor cortex), subthalamic nucleus/zona incerta, and red nucleus and bilateral sensory cortex. In conclusion, CCI resulted in increased functional recruitment of contralesional motor cortex and bilateral subcortical motor regions, as well as recruitment of the cerebellar–thalamocortical circuit and contralesional sensory cortex. This phenomenon, augmented by physostigmine, may partially compensate motor deficits. FC decreased inter-hemispherically and in negative, but not positive, intra-hemispherical FC, and it was not affected by physostigmine. Circuit-based approaches into functional brain reorganization may inform future behavioral or molecular strategies to augment targeted neurorehabilitation.

We studied the role of PI3K cascade in the basolateral amygdala (BLA) and the infralimbic region of the medial prefrontal cortex (IL-mPFC), in contextual fear learning and extinction in the rat. To that end, we micro-infused the phosphoinositide-3-kinase (PIK3) inhibitor LY294002 into either the mPFC or the BLA. Infusion of LY294002 into the BLA following fear conditioning was associated with enhanced freezing levels and impaired extinction in the subsequent sessions. Similarly, inhibition of PI3K in the BLA before the retrieval of fear memory was associated with impaired retrieval of the fear memory, which was expressed as reduced freezing levels that persisted over 2 d. In the IL-mPFC, only consolidation of fear extinction was impaired: micro-infusion of PI3K inhibitor following the retrieval of fear was associated with impaired extinction on the following days. These results indicate differences in the temporal parameters of the effects of PI3K inhibition in the IL-mPFC and in the BLA, which suggest differential involvement of these structures in long-term fear and in extinction of fear memory. Our findings provide additional evidence for the critical roles played by PI3K in intact formation of fear memory and in its extinction and add new evidence for a role of PI3K in consolidation of memory of extinction. Better understanding of the differential involvement of the PI3K cascade during acquisition and extinction of fear conditioning in the mPFC-amygdala circuit could potentially contribute to the understanding and treatment of anxiety disorders.

The assembly of neuronal circuits during development requires the precise navigation of axons, which is controlled by attractive and repulsive guidance cues. In the developing spinal cord, ephrinB3 functions as a short-range repulsive cue that prevents EphA4 receptor-expressing corticospinal tract and spinal interneuron axons from crossing the midline, ensuring proper formation of locomotor circuits. Here we report that the small GTPase RhoA, a key regulator of cytoskeletal dynamics, is also required for ephrinB3/EphA4-dependent locomotor circuit formation. Deletion of RhoA from neural progenitor cells results in mice that exhibit a rabbit-like hopping gait, which phenocopies mice lacking ephrinB3 or EphA4. Consistent with this locomotor defect, we found that corticospinal tract axons and spinal interneuron projections from RhoA-deficient mice aberrantly cross the spinal cord midline. Furthermore, we determined that loss of RhoA blocks ephrinB3-induced growth cone collapse of cortical axons and disrupts ephrinB3 expression at the spinal cord midline. Collectively, our results demonstrate that RhoA is essential for the ephrinB3/EphA4-dependent assembly of cortical and spinal motor circuits that control normal locomotor behavior.

Nitric oxide (NO) is a gaseous neurotransmitter that plays a significant role in the establishment and refinement of functional neural circuits. Genetic and post-mortem studies have suggested that neuronal NO synthase (NOS-1) activity may be compromised in frontal and temporal lobes, and related structures, in schizophrenia. The goal of this study was to determine if there is a link between neonatal disruptions in NO signalling and disturbances in the development and function of prefrontal–temporolimbic circuits. Neonatal rats were injected on postnatal days PD3–5 with the selective NOS-1 inhibitor N ω -propyl-l-arginine (NPA) and tested in adulthood (⩾PD60) or as juveniles (PD30). Adult rats treated with NPA as neonates exhibited increased amphetamine-induced locomotion compared to animals receiving vehicle as neonates, whereas this was not observed in juvenile rats treated with NPA as neonates. Adult rats exposed to NPA as neonates also exhibited deficits in social interaction and short-term recognition memory, as well as reduced brain weight, compared to vehicle-treated controls. Finally, neonatal NPA exposure increased the responsiveness of nucleus accumbens neurons to prefrontal cortical input and disrupted the modulation of cortico-accumbens circuits by hippocampal afferents that is normally observed in adult animals. These results show for the first time that neonatal inhibition of NOS-1 during a critical neurodevelopmental period leads to aberrant behaviours that manifest in adulthood, as well as electrophysiological abnormalities in prefrontal–temporolimbic circuits. Greater understanding of the role of NOS-1 in the development of these circuits will shed light on how developmental insults translate to pathophysiology associated with schizophrenia.

In this paper we propose and analyze parameter-free models for the mitogen-activated protein kinase (MAPK) pathway in PC12 rat neural cells. Experiments show that the dynamic behavior of this pathway depends on the input growth factor. The response to epidermal growth factor (EGF) is a short peak followed by a relaxation, while the response to nerve growth factor (NGF) is sustained. In the latter case, the system can be driven to a new state, which persists after the stimulus has vanished. Ultimately, these dynamic behaviors correspond to different cell fates: EFG stimulation induces proliferation, while NGF stimulation induces differentiation. The biochemical mechanisms responsible for the different input-dependent dynamic response are still unclear. One hypothesis is that each input generates a specific interaction topology among the kinases. Starting from experimental results that support this hypothesis, we derive and analyze qualitative models for the two network topologies. Our approach is based on invariant set theory and non-smooth Lyapunov functions. We demonstrate analytically that the network behaviors and stability properties are structurally dependent on the topology, and do not depend on specific parameter values of the underlying biochemical interactions.

Earlier studies in zebrafish have revealed that acutely given ethanol has a stimulatory effect on locomotion in fish larvae but the mechanism of this effect has not been revealed. We studied the effects of ethanol concentrations between 0.75 and 3.00% on 7-day-old larval zebrafish (Danio rerio) of the Turku strain. At 0.75-3% concentrations ethanol increased swimming speed during the first minute. At 3% the swimming speed decreased rapidly after the first minute, whereas at 0.75 and 1.5% a prolonged increase in swimming speed was seen. At the highest ethanol concentration dopamine levels decreased significantly after a 10-min treatment. We found that ethanol upregulates key genes involved in the biosynthesis of histamine (hdc) and dopamine (th1 and th2) following a short 10-min ethanol treatment, measured by qPCR. Using in situ hybridization and immunohistochemistry, we further discovered that the morphology of the histaminergic and dopaminergic neurons and networks in the larval zebrafish brain was unaffected by both the 10-min and a longer 30-min treatment. The results suggest that acute ethanol rapidly decreases dopamine levels, and activates both forms or th to replenish the dopamine stores within 30 min. The dynamic changes in histaminergic and dopaminergic system enzymes occurred in the same cells which normally express the transcripts. As both dopamine and histamine are known to be involved in the behavioral effects of ethanol and locomotor stimulation, these results suggest that rapid adaptations of these networks are associated with altered locomotor activity.