Synapse independence breaks down during highly synchronous network activity in the rat hippocampus

Adult neurogenesis is the multistage process of generating neurons from adult neural stem cells. Accumulating evidence indicates that GABAergic depolarization is an important regulator of this process. Here, we examined GABAergic signaling to newly generated granule cells (GCs) of the adult mouse dentate gyrus. We show that the first synaptic currents in newborn GCs are generated by activation of GABA A receptors by GABA with a spatiotemporal profile suggestive of transmitter spillover. However, the GABAergic response is not attributable to spillover from surrounding perisomatic synapses. Rather, our results suggest that slow synaptic responses in newborn GCs are generated by dedicated inputs that produce a relatively low concentration of GABA at postsynaptic receptors, similar to slow IPSCs in mature GCs. This form of synaptic signaling drives robust phasic depolarization of newborn GCs when the interneuron network is synchronously active, revealing a potential mechanism that translates hippocampal activity into regulation of adult neurogenesis via synaptic release of GABA.

Section: Resultssupporting

confidence: 52%

Input-Specific GABAergic Signaling to Newborn Neurons in Adult Dentate Gyrus

Markwardt¹,

Wadiche²,

Overstreet-Wadiche³

2009

“…For instance, multi-vesicular glutamate release at FS cell synapses (Watanabe et al, 2005) may produce a high glutamate concentration transient in the synaptic cleft thus displacing more strongly the competitive antagonist AP5 at FS versus pyramidal cell synapses. To estimate the NMDAR contribution independently of AP5 effects, we used CNQX, a high affinity AMPAR antagonist whose efficacy is less affected by the cleft glutamate concentration (Biro and Nusser, 2005). Because detection of NMDAR-mediated sEPSCs after CNQX application was unreliable (Supplemental Figure 2), we studied EPSCs evoked with focal extracellular stimulation (eEPSCs) at low intensity, to minimize polysynaptic transmission, which in low Mg 2+ is enhanced by NMDAR-mediated excitation (Thomson and West, 1986).…”

Section: Resultsmentioning

confidence: 99%

Glutamate Receptor Subtypes Mediating Synaptic Activation of Prefrontal Cortex Neurons: Relevance for Schizophrenia

Rotaru¹,

Yoshino²,

Lewis³

et al. 2011

137

159

Schizophrenia may involve hypofunction of NMDAR-mediated signaling, and alterations in parvalbumin-positive fast-spiking (FS) GABA neurons that may cause abnormal gamma oscillations. It was recently hypothesized that prefrontal cortex (PFC) FS neuron activity is highly dependent on NMDAR activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDAR hypofunction. However, NMDARs are abundant in synapses onto PFC pyramidal neurons, thus a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDARs. We examined the AMPAR and NMDAR contribution to synaptic activation of FS neurons and pyramidal cells in the PFC of adult mice. In FS neurons, EPSCs had fast decay and weak NMDAR contribution whereas in pyramidal cells EPSCs were significantly prolonged by NMDAR-mediated currents. Moreover, the AMPAR/NMDAR EPSC ratio was higher in FS cells. NMDAR antagonists decreased EPSPs and EPSP-spike coupling more strongly in pyramidal cells than in FS neurons, showing that FS neuron activation is less NMDAR-dependent than pyramidal cell excitation. The precise EPSP-spike coupling produced by fast-decaying EPSCs in FS cells may be important for network mechanisms of gamma oscillations based on feedback inhibition. To test this possibility, we used simulations in a computational network of reciprocally-connected FS neurons and pyramidal cells and found that brief AMPAR-mediated FS neuron activation is crucial to synchronize, via feedback inhibition, pyramidal cells in the gamma frequency band. Our results raise interesting questions about the mechanisms that might link NMDAR hypofunction to alterations of FS neurons in schizophrenia.

“…Under physiological conditions, glutamate is released into the extrasynaptic space by spillover from synapses (Asztely et al, 1997; Biro and Nusser, 2005; Sem'yanov, 2005), exocytosis from astrocytes (Santello and Volterra, 2008), and active transport by the cystine-glutamate antiporter (Baker et al, 2002). Extrasynaptic glutamate as measured by our microelectrodes is affected by block of action potentials by tetrodotoxin, indicating that it reflects neuronal activity (Day et al, 2006; Hascup et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Homeostasis of Extracellular Glutamate in the Rat Cerebral Cortex across Sleep and Waking States

Dash¹,

Douglas²,

Vyazovskiy³

et al. 2009

229

199

Neuronal firing patterns, neuromodulators, and cerebral metabolism change across sleep-waking states, and the synaptic release of glutamate is critically involved in these processes. Extrasynaptic glutamate can also affect neural function and may be neurotoxic, but whether and how extracellular glutamate is regulated across sleep-waking states is unclear. To assess the effect of behavioral state on extracellular glutamate at high temporal resolution, we recorded glutamate concentration in prefrontal and motor cortex using fixedpotential amperometry in freely behaving rats. Simultaneously, we recorded local field potentials (LFPs) and electroencephalograms (EEGs) from contralateral cortex. We observed dynamic, progressive changes in the concentration of glutamate that switched direction as a function of behavioral state. Specifically, the concentration of glutamate increased progressively during waking (0.329 Ϯ 0.06%/min) and rapid eye movement (REM) sleep (0.349 Ϯ 0.13%/min). This increase was opposed by a progressive decrease during non-REM (NREM) sleep (0.338 Ϯ 0.06%/min). During a 3 h sleep deprivation period, glutamate concentrations initially exhibited the progressive rise observed during spontaneous waking. As sleep pressure increased, glutamate concentrations ceased to increase and began decreasing despite continuous waking. During NREM sleep, the rate of decrease in glutamate was positively correlated with sleep intensity, as indexed by LFP slow-wave activity. The rate of decrease doubled during recovery sleep after sleep deprivation. Thus, the progressive increase in cortical extrasynaptic glutamate during EEG-activated states is counteracted by a decrease during NREM sleep that is modulated by sleep pressure. These results provide evidence for a long-term homeostasis of extracellular glutamate across sleep-waking states.