Differentiation of Hebbian and homeostatic plasticity mechanisms within layer 5 visual cortex neurons.

Cortical layer 5 contains two major types of projection neuron known as IB (intrinsic bursting) cells that project sub-cortically and RS (regular spiking) cells that project between cortical areas. This study describes the plasticity properties of RS and IB cells in the mouse visual cortex during the critical period for ocular dominance plasticity. We find that RS neurons exhibit synaptic depression in response to both dark exposure (DE) and monocular deprivation (MD), and their homeostatic recovery from depression is dependent on TNF-α.

Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness.

A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route.

Mechanisms underlying the role of DISC1 in synaptic plasticity.

Disrupted in schizophrenia 1 (DISC1) is an important hub protein, forming multimeric complexes by self-association and interacting with a large number of synaptic and cytoskeletal molecules. The synaptic location of DISC1 in the adult brain suggests a role in synaptic plasticity, and indeed, a number of studies have discovered synaptic plasticity impairments in a variety of different DISC1 mutants. This review explores the possibility that DISC1 is an important molecule for organizing proteins involved in synaptic plasticity and examines why mutations in DISC1 impair plasticity.

Severe Intellectual Disability and Enhanced Gamma-Aminobutyric Acidergic Synaptogenesis in a Novel Model of Rare RASopathies.

Background: Dysregulation of Ras-extracellular signal-related kinase (ERK) signaling gives rise to RASopathies, a class of neurodevelopmental syndromes associated with intellectual disability. Recently, much attention has been directed at models bearing mild forms of RASopathies whose behavioral impairments can be attenuated by inhibiting the Ras-ERK cascade in the adult. Little is known about the brain mechanisms in severe forms of these disorders.

NEURODEVELOPMENT. Adult cortical plasticity depends on an early postnatal critical period.

Development of the cerebral cortex is influenced by sensory experience during distinct phases of postnatal development known as critical periods. Disruption of experience during a critical period produces neurons that lack specificity for particular stimulus features, such as location in the somatosensory system. Synaptic plasticity is the agent by which sensory experience affects cortical development.

Derangement of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia.

Background: Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease.

The role of nitric oxide in pre-synaptic plasticity and homeostasis.

Since the observation that nitric oxide (NO) can act as an intercellular messenger in the brain, the past 25 years have witnessed the steady accumulation of evidence that it acts pre-synaptically at both glutamatergic and GABAergic synapses to alter release-probability in synaptic plasticity. NO does so by acting on the synaptic machinery involved in transmitter release and, in a coordinated fashion, on vesicular recycling mechanisms. In this review, we examine the body of evidence for NO acting as a retrograde factor at synapses, and the evidence from in vivo and in vitro studies that specifically establish NOS1 (neuronal nitric oxide synthase) as the important isoform of NO synthase in this process.

The role of nitric oxide synthase in cortical plasticity is sex specific.

Nitric oxide synthase-1 (NOS1) is involved in several forms of plasticity including hippocampal-dependent learning and memory, experience-dependent plasticity in the barrel cortex, and long-term potentiation (LTP) in the hippocampus and neocortex. NOS1 also contributes to ischemic damage during stroke and has a stronger deleterious effect in males than females. We therefore investigated whether the role of NOS1 in plasticity might also be sex specific.

Experience-dependent plasticity acts via GluR1 and a novel neuronal nitric oxide synthase-dependent synaptic mechanism in adult cortex.

Synaptic plasticity directs development of the nervous system and is thought to underlie memory storage in adult animals. A great deal of our current understanding of the role of AMPA receptors in synaptic plasticity comes from studies on developing cortex and cell cultures. In the present study, we instead focus on plasticity in mature neurons in the neocortex of adult animals.

Anatomical and sensory experiential determinants of synaptic plasticity in layer 2/3 pyramidal neurons of mouse barrel cortex.

A minority of layer 2/3 (L2/3) pyramidal neurons exhibit spike-timing-dependent long-term potentiation (LTP) in normally reared adolescent mice. To determine whether particular subtypes of L2/3 neurons have a greater capacity for LTP than others, we correlated the morphological and electrophysiological properties of L2/3 neurons with their ability to undergo LTP by using a spike-timing-dependent protocol applied via layer 4 inputs from the neighboring barrel column. No correlation was found between the incidence of LTP and the cell's electrophysiological properties, nor with their laminar or columnar location.

Quantal analysis reveals a functional correlation between presynaptic and postsynaptic efficacy in excitatory connections from rat neocortex.

At many central synapses, the presynaptic bouton and postsynaptic density are structurally correlated. However, it is unknown whether this correlation extends to the functional properties of the synapses. To investigate this, we made recordings from synaptically coupled pairs of pyramidal neurons in rat visual cortex.

Postsynaptic action potentials are required for nitric-oxide-dependent long-term potentiation in CA1 neurons of adult GluR1 knock-out and wild-type mice.

Neocortical long-term potentiation (LTP) consists of both presynaptic and postsynaptic components that rely on nitric oxide (NO) and the GluR1 subunit of the AMPA receptor, respectively. In this study, we found that hippocampal LTP, induced by theta-burst stimulation in mature (>8-week-old) GluR1 knock-out mice was almost entirely NO dependent and involved both the alpha splice variant of NO synthase-1 and the NO synthase-3 isoforms of NO synthase. Theta-burst induced LTP was also partly NO-dependent in wild-type mice and made up approximately 50% of the potentiation 2 h after tetanus.

Sensory deprivation unmasks a PKA-dependent synaptic plasticity mechanism that operates in parallel with CaMKII.

Calcium/calmodulin kinase II (CaMKII) is required for LTP and experience-dependent potentiation in the barrel cortex. Here, we find that whisker deprivation increases LTP in the layer IV to II/III pathway and that PKA antagonists block the additional LTP. No LTP was seen in undeprived CaMKII-T286A mice, but whisker deprivation again unmasked PKA-sensitive LTP.

Laminar analysis of the role of GluR1 in experience-dependent and synaptic depression in barrel cortex.

Several synaptic depression mechanisms have been described for the hippocampus, cerebellum and neocortex in vitro, but little is known about which, if any, are engaged during experience-dependent depression (EDD). We found that EDD in the mouse barrel cortex depends on the AMPA subunit GluR1 in layers II/III and IV, but not in layer V, and that long-term depression is also GluR1 dependent in the IV-II/III, but not II/III-V, pathway.

Presynaptic efficacy directs normalization of synaptic strength in layer 2/3 rat neocortex after paired activity.

Paired neuronal activity is known to induce changes in synaptic strength that result in the synapse in question having different properties to unmodified synapses. Here we show that in layer 2/3 excitatory connections in young adult rat cortex paired activity acts to normalize the strength and quantal parameters of connections. Paired action potential firing produces long-term potentiation in only a third of connections, whereas a third remain with their amplitude unchanged and a third exhibit long-term depression.

The role of nitric oxide and GluR1 in presynaptic and postsynaptic components of neocortical potentiation.

In this study, we investigated the mechanisms underlying synaptic plasticity at the layer IV to II/III pathway in barrel cortex of mice aged 6-13 weeks. This pathway is one of the likely candidates for expression of experience-dependent plasticity in the barrel cortex and may serve as a model for other IV to II/III synapses in the neocortex. We found that postsynaptic autocamtide-2-inhibitory peptide is sufficient to block long-term potentiation (LTP) (IC50 of 500 nm), implicating postsynaptic calcium/calmodulin-dependent kinase II in LTP induction.

Extracellular calcium regulates postsynaptic efficacy through group 1 metabotropic glutamate receptors.

Bursts of synaptic transmission are known to induce transient depletion of Ca2+ within the synaptic cleft. Although Ca2+ depletion has been shown to lower presynaptic release probability, effects on the postsynaptic cell have not been reported. In this study, we show that physiologically relevant reductions in extracellular Ca2+ lead to a decrease in synaptic strength between synaptically coupled layer 2/3 cortical pyramidal neurons.

Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability.

Neuroprotection can be induced by low doses of NMDA, which activate both synaptic and extrasynaptic NMDA receptors. This is in apparent contradiction with our recent findings that extrasynaptic NMDA receptor signaling exerts a dominant inhibitory effect on prosurvival signaling from synaptic NMDA receptors. Here we report that exposure to low preconditioning doses of NMDA results in preferential activation of synaptic NMDA receptors because of a dramatic increase in action potential firing.

Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection.

The mechanism by which physiological synaptic NMDA receptor activity promotes neuronal survival is not well understood. Here, we show that that an episode of synaptic activity can promote neuroprotection for a long time after that activity has ceased. This long-lasting or "late phase" of neuroprotection is dependent on nuclear calcium signaling and cAMP response element (CRE)-mediated gene expression.

Neocortical long-term potentiation and experience-dependent synaptic plasticity require alpha-calcium/calmodulin-dependent protein kinase II autophosphorylation.

Experience-dependent plasticity can be induced in the barrel cortex by removing all but one whisker, leading to potentiation of the neuronal response to the spared whisker. To determine whether this form of potentiation depends on synaptic plasticity, we studied long-term potentiation (LTP) and sensory-evoked potentials in the barrel cortex of alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII)T286A mutant mice. We studied three different forms of LTP induction: theta-burst stimulation, spike pairing, and postsynaptic depolarization paired with low-frequency presynaptic stimulation.