How feedback inhibition shapes spike-timing-dependent plasticity and its implications for recent Schizophrenia models

It has been shown that plasticity is not a fixed property but, in fact, changes depending on the location of the synapse on the neuron and/or changes of biophysical parameters. Here we investigate how plasticity is shaped by feedback inhibition in a cortical microcircuit. We use a differential Hebbian learning rule to model spike-timing dependent plasticity and show analytically that the feedback inhibition shortens the time window for LTD during spike-timing dependent plasticity but not for LTP. We then use a realistic GENESIS model to test two hypothesis about interneuron hypofunction and conclude that a reduction in GAD67 is the most likely candidate as the cause for hypofrontality as observed in Schizophrenia

Modulation of Spike-Timing Dependent Plasticity: Towards the Inclusion of a Third Factor in Computational Models

In spike-timing dependent plasticity (STDP) change in synaptic strength depends on the timing of pre- vs. postsynaptic spiking activity. Since STDP is in compliance with Hebb’s postulate, it is considered one of the major mechanisms of memory storage and recall. STDP comprises a system of two coincidence detectors with N-methyl-D-aspartate receptor (NMDAR) activation often posited as one of the main components. Numerous studies have unveiled a third component of this coincidence detection system, namely neuromodulation and glia activity shaping STDP. Even though dopaminergic control of STDP has most often been reported, acetylcholine, noradrenaline, nitric oxide (NO), brain-derived neurotrophic factor (BDNF) or gamma-aminobutyric acid (GABA) also has been shown to effectively modulate STDP. Furthermore, it has been demonstrated that astrocytes, via the release or uptake of glutamate, gate STDP expression. At the most fundamental level, the timing properties of STDP are expected to depend on the spatiotemporal dynamics of the underlying signaling pathways. However in most cases, due to technical limitations experiments grant only indirect access to these pathways. Computational models carefully constrained by experiments, allow for a better qualitative understanding of the molecular basis of STDP and its regulation by neuromodulators. Recently, computational models of calcium dynamics and signaling pathway molecules have started to explore STDP emergence in ex and in vivo-like conditions. These models are expected to reproduce better at least part of the complex modulation of STDP as an emergent property of the underlying molecular pathways. Elucidation of the mechanisms underlying STDP modulation and its consequences on network dynamics is of critical importance and will allow better understanding of the major mechanisms of memory storage and recall both in health and disease

The Effects of NMDA Subunit Composition on Calcium Influx and Spike Timing-Dependent Plasticity in Striatal Medium Spiny Neurons

Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptor's response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi-channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR-mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development

Questions about STDP as a General Model of Synaptic Plasticity

According to spike-timing-dependent plasticity (STDP), the timing of the Na+ spike relative to the EPSP determines whether LTP or LTD will occur. Here, we review our reservations about STDP. Most investigations of this process have been done under conditions in which the spike is evoked by postsynaptic current injection. Under more realistic conditions, in which the spike is evoked by the EPSP, the results do not generally support STDP. For instance, low-frequency stimulation of a group of synapses can cause LTD, not the LTP predicted by the pre-before-post sequence in STDP; this is true regardless of whether or not the EPSP is large enough to produce a Na+ spike. With stronger or more frequent stimulation, LTP can be induced by the same pre-before-post timing, but in this case block of Na+ spikes does not necessarily prevent LTP induction. Thus, Na+ spikes may facilitate LTP and/or LTD under some conditions, but they are not necessary, a finding consistent with their small size relative to the EPSP in many parts of pyramidal cell dendrites. The nature of the dendritic depolarizing events that control bidirectional plasticity is of central importance to understanding neural function. There are several candidates, including backpropagating action potentials, but also dendritic Ca2+ spikes, the AMPA receptor-mediated EPSP, and NMDA receptor-mediated EPSPs or spikes. These often appear to be more important than the Na+ spike in providing the depolarization necessary for plasticity. We thus feel that it is premature to accept STDP-like processes as the major determinant of LTP/LTD

Detailed dendritic excitatory/inhibitory balance through heterosynaptic spike-timing-dependent plasticity

The balance between excitatory and inhibitory inputs is a key feature of cortical dynamics. Such a balance is arguably preserved in dendritic branches, yet its underlying mechanism and functional roles remain unknown. In this study, we developed computational models of heterosynaptic spike-timing-dependent plasticity (STDP) to show that the excitatory/inhibitory balance in dendritic branches is robustly achieved through heterosynaptic interactions between excitatory and inhibitory synapses. The model reproduces key features of experimental heterosynaptic STDP well, and provides analytical insights. Furthermore, heterosynaptic STDP explains how the maturation of inhibitory neurons modulates the selectivity of excitatory neurons for binocular matching in the critical period plasticity. The model also provides an alternative explanation for the potential mechanism underlying the somatic detailed balance that is commonly associated with inhibitory STDP. Our results propose heterosynaptic STDP as a critical factor in synaptic organization and the resultant dendritic computation

Astrocytes: Orchestrating synaptic plasticity?

Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes

GABA Regulation of Burst Firing in Hippocampal Astrocyte Neural Circuit: A Biophysical Model

It is now widely accepted that glia cells and gamma-aminobutyric acidergic (GABA) interneurons dynamically regulate synaptic transmission and neuronal activity in time and space. This paper presents a biophysical model that captures the interaction between an astrocyte cell, a GABA interneuron and pre/postsynaptic neurons. Specifically, GABA released from a GABA interneuron triggers in astrocytes the release of calcium (Ca2+) from the endoplasmic reticulum via the inositol 1, 4, 5-trisphosphate (IP3) pathway. This results in gliotransmission which elevates the presynaptic transmission probability rate (PR) causing weight potentiation and a gradual increase in postsynaptic neuronal firing, that eventually stabilizes. However, by capturing the complex interactions between IP3, generated from both GABA and the 2-arachidonyl glycerol (2-AG) pathway, and PR, this paper shows that this interaction not only gives rise to an initial weight potentiation phase but also this phase is followed by postsynaptic bursting behavior. Moreover, the model will show that there is a presynaptic frequency range over which burst firing can occur. The proposed model offers a novel cellular level mechanism that may underpin both seizure-like activity and neuronal synchrony across different brain regions