Balancing Excitation and Inhibition

In this issue of Neuron, D’amour and Froemke (2015) examine how inhibitory spike-time-dependent plasticity (STDP) interacts with co-activated excitatory STDP to regulate excitatory-inhibitory balance in auditory cortex

Inactivation of presenilins causes pre-synaptic impairment prior to post-synaptic dysfunction

Synaptic dysfunction is widely thought to be a pathogenic precursor to neurodegeneration in Alzheimer’s disease (AD), and the extent of synaptic loss provides the best correlate for the severity of dementia in AD patients. Presenilins 1 and 2 are the major causative genes of early‐onset familial AD. Conditional inactivation of presenilins in the adult cerebral cortex results in synaptic dysfunction and memory impairment, followed by age‐dependent neurodegeneration. To characterize further the consequence of presenilin inactivation in the synapse, we evaluated the temporal development of pre‐synaptic and post‐synaptic deficits in the Schaeffer‐collateral pathway of presenilin conditional double knockout (PS cDKO) mice prior to onset of neurodegeneration. Following presenilin inactivation at 4 weeks, synaptic facilitation and probability of neurotransmitter release are impaired in PS cDKO mice at 5 weeks of age, whereas post‐synaptic NMDA receptor (NMDAR)‐mediated responses are normal at 5 weeks but impaired at 6 weeks of age. Long‐term potentiation induced by theta burst stimulation is also reduced in PS cDKO mice at 6 weeks of age. These results show that loss of presenilins results in pre‐synaptic deficits in short‐term plasticity and probability of neurotransmitter release prior to post‐synaptic NMDAR dysfunction, raising the possibility that presenilins may regulate post‐synaptic NMDAR function in part via a trans‐synaptic mechanism.This work was supported by the National Institute of Health NS041783 (to J.S.). We would like to thank Xiaoyan Zou and Huailong Zhao for technical assistance. (NS041783 - National Institute of Health)Published versio

Dark rearing alters the development of GABAergic transmission in visual cortex

We studied the role of sensory experience in the maturation of GABAergic circuits in the rat visual cortex. Between the time at which the eyes first open and the end of the critical period for experience-dependent plasticity, the total GABAergic input converging into layer II/III pyramidal cells increases threefold. We propose that this increase reflects changes in the number of quanta released by presynaptic axons. Here, we show that the developmental increase in GABAergic input is prevented in animals deprived of light since birth but not in animals deprived of light after a period of normal experience. Thus, sensory experience appears to play a permissive role in the maturation of intracortical GABAergic circuits. Key words: synaptic inhibition; critical period; IPSC; EPSC; plasticity; sensory experience Sensory experience during the postnatal critical period is essentia

Timing is not Everything: Neuromodulation Opens the STDP Gate

Spike timing dependent plasticity (STDP) is a temporally specific extension of Hebbian associative plasticity that has tied together the timing of presynaptic inputs relative to the postsynaptic single spike. However, it is difficult to translate this mechanism to in vivo conditions where there is an abundance of presynaptic activity constantly impinging upon the dendritic tree as well as ongoing postsynaptic spiking activity that backpropagates along the dendrite. Theoretical studies have proposed that, in addition to this pre- and postsynaptic activity, a “third factor” would enable the association of specific inputs to specific outputs. Experimentally, the picture that is beginning to emerge, is that in addition to the precise timing of pre- and postsynaptic spikes, this third factor involves neuromodulators that have a distinctive influence on STDP rules. Specifically, neuromodulatory systems can influence STDP rules by acting via dopaminergic, noradrenergic, muscarinic, and nicotinic receptors. Neuromodulator actions can enable STDP induction or – by increasing or decreasing the threshold – can change the conditions for plasticity induction. Because some of the neuromodulators are also involved in reward, a link between STDP and reward-mediated learning is emerging. However, many outstanding questions concerning the relationship between neuromodulatory systems and STDP rules remain, that once solved, will help make the crucial link from timing-based synaptic plasticity rules to behaviorally based learning

Timing is not Everything: Neuromodulation Opens the STDP Gate

Spike timing dependent plasticity (STDP) is a temporally specific extension of Hebbian associative plasticity that has tied together the timing of presynaptic inputs relative to the postsynaptic single spike. However, it is difficult to translate this mechanism to in vivo conditions where there is an abundance of presynaptic activity constantly impinging upon the dendritic tree as well as ongoing postsynaptic spiking activity that backpropagates along the dendrite. Theoretical studies have proposed that, in addition to this pre- and postsynaptic activity, a “third factor” would enable the association of specific inputs to specific outputs. Experimentally, the picture that is beginning to emerge, is that in addition to the precise timing of pre- and postsynaptic spikes, this third factor involves neuromodulators that have a distinctive influence on STDP rules. Specifically, neuromodulatory systems can influence STDP rules by acting via dopaminergic, noradrenergic, muscarinic, and nicotinic receptors. Neuromodulator actions can enable STDP induction or – by increasing or decreasing the threshold – can change the conditions for plasticity induction. Because some of the neuromodulators are also involved in reward, a link between STDP and reward-mediated learning is emerging. However, many outstanding questions concerning the relationship between neuromodulatory systems and STDP rules remain, that once solved, will help make the crucial link from timing-based synaptic plasticity rules to behaviorally based learning

Absence of long-term depression in the visual cortex of glutamic Acid decarboxylase-65 knock-out mice.

Long-term depression (LTD) is widely considered a mechanism for experience-induced synaptic weakening in the brain. Recent in vivo studies on glutamic acid decarboxylase [GAD 65 (/)] knock-out mice indicates that GABAergic synaptic inhibition is also required for the normal weakening of deprived inputs in the visual cortex. To better understand how GABAergic inhibition might control plasticity, we assessed the status of synaptic inhibition and LTD in visual cortical slices of GAD 65 knock-out mice. We found the following: (1) the efficacy of GABAergic synapses during repetitive activation is reduced in GAD 65 (/) mice; (2) the induction of LTD is impaired in the visual cortex of GAD 65 (/) mice; and (3) chronic, but not acute, treatment with the benzodiazepine agonist diazepam restores LTD in GAD 65 (/) mice. These results suggest that a certain inhibitory tone is required for the induction of LTD in visual cortex. We propose that the lack of visual cortical LTD in GAD 65 (/) may account for the lack of experience-dependent plasticity in these mice

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory

Neonatal hypoxic-ischemic (HI) injury leads to deficits in hippocampal parvalbumin (PV)+ interneurons (INs) and working memory. Therapeutic hypothermia (TH) does not prevent these deficits. ErbB4 supports maturation and maintenance of PV+ IN. Thus, we hypothesized that neonatal HI leads to persistent deficits in PV+ INs, working memory and synaptic plasticity associated with ErbB4 dysregulation despite TH. P10 HI-injured mice were randomized to normothermia (NT, 36 °C) or TH (31 °C) for 4 h and compared to sham. Hippocampi were studied for α-fodrin, glial fibrillary acidic protein (GFAP), and neuroregulin (Nrg) 1 levels; erb-b2 receptor tyrosine kinase 4 (ErbB4)/ Ak strain transforming (Akt) activation; and PV, synaptotagmin (Syt) 2, vesicular-glutamate transporter (VGlut) 2, Nrg1, and ErbB4 expression in coronal sections. Extracellular field potentials and behavioral testing were performed. At P40, deficits in PV+ INs correlated with impaired memory and coincided with blunted long-term depression (LTD), heightened long-term potentiation (LTP) and increased Vglut2/Syt2 ratio, supporting excitatory-inhibitory (E/I) imbalance. Hippocampal Nrg1 levels were increased in the hippocampus 24 h after neonatal HI, delaying the decline documented in shams. Paradoxically ErbB4 activation decreased 24 h and again 30 days after HI. Neonatal HI leads to persistent deficits in hippocampal PV+ INs, memory, and synaptic plasticity. While acute decreased ErbB4 activation supports impaired maturation and survival after HI, late deficit reemergence may impair PV+ INs maintenance after HI

Multiple receptors coupled to phospholipase C gate long-term depression in visual cortex

Mind/Brain Institute and Department of Neurosciences and 2Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland 21218, and 3National CRI Center for Calcium and Learning, Korea Institute of Science and Technology, Cheongryang, Seoul 136-791, Korea Long-term depression (LTD) in sensory cortices depends on the activation of NMDA receptors. Here, we report that in visual cortical slices, the induction of LTD (but not long-term potentiation) also requires the activation of receptors coupled to the phospholipase C (PLC) pathway. Using immunolesions in combination with agonists and antagonists, we selectively manipulated the activation of 1 adrenergic, M1 muscarinic, and mGluR5 glutamatergic receptors. Inactivation of these PLC-coupled receptors prevents the induction of LTD, but only when the three receptors were inactivated together. LTD is fully restored by activating any one of them or by supplying intracellular D-myo-inositol-1,4,5-triphosphate (IP3). LTD was also impaired by intracellular application of PLC or IP3 receptor blockers, and it was absent in mice lacking PLC1, the predominant PLC isoform in the forebrain. We propose that visual cortical LTD requires a minimum of PLC activity that can be supplied independently by at least three neurotransmitter systems. This essential requirement places PLC-linked receptors in a unique position to control the induction of LTD and provides a mechanism for gating visual cortical plasticity via extra-retinal inputs in the intact organism

Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice.

Accumulation of -amyloid (A ) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimers disease (AD). Presenilin 1 (PS1) plays an essential role in the -secretase cleavage of the amyloid precursor protein (APP) and the generation of A peptides. Reduction of A generation via the inhibition of -secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out (PS1 cKO) mice can prevent the accumulation ofA peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively prevented the accumulation of A peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of A via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.This work was supported by National Institute of Neurological Disorders and Stroke Grant R01NS041783 (J.S.), the Alzheimers Association (C.A.S., J.S.), the Medical Research Council, and the Alzheimers Research Trust (R.G.M.M). We thank L. Mucke for the APP transgenic mice, D. Selkoe for the C7 and A antibodies, M. Shoji for the Saeko antiserum, and W. Xia and J. Zheng for ELISA. We are grateful to V. Beglopoulos, W. Cheng, M. Goldberg, and C. Lemere for assistance

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation