Synapse-Specific Adaptations to Inactivity in Hippocampal Circuits Achieve Homeostatic Gain Control while Dampening Network Reverberation

“This sets the interpretation of our data apart from any developmental influence; this is of relevance because responses to inactivity may vary widely depending on the maturity of the neural network (Burrone et al., 2002; Hartman et al., 2006; Karmarkar and Buonomano, 2006; Kirov et al., 2004).”

“…demonstrated in a variety of central neurons both in vitro and in vivo, including neocortical and hippocampal pyramidal neurons and spinal neurons (Desai et al. 2002, Goel & Lee 2007, Kim & Tsien 2008, Knogler et al. 2010; O’Brien et al. 1998, Stellwagen & Malenka 2006, Turrigiano et al. 1998).”

“However, uniform synaptic scaling may produce instability in recurrent circuits (Blanco et al., 2015; Buonomano, 2005; Kim and Tsien, 2008; Mitra et al., 2012).”

“For a given retrograde messenger, the degree of localization of retrograde signaling, and thus its synapse specificity, depends on several factors.”

“Indeed, cell type–specific differences in the locus of expression of homeostatic plasticity have been documented (43, 53).”

“Synaptic scaling occurs in both cultured neurons and in hippocampal slices, although in slice it appears to be heterogeneous, varying in both a target- and afferent-specific manner (Kim and Tsien, 2008).”

“However, such uniformity of changes in synaptic strength across all synapses of a neuron during synaptic scaling has not been universally observed (7–9) and intriguing input-specific features have been reported to occur during global synaptic scaling (10).”

“The importance of synaptic organization is further highlighted by work in organotypic hippocampal and cortical cultures showing that different types of synaptic inputs within a same circuit adapt differently to global activity deprivation [41,42].”

“…Craig et al., 1994; Galante et al., 2000; Gomperts 304 Neuron 94, 304–311, April 19, 2017 ª 2017 Elsevier Inc. et al., 2000; Harms and Craig, 2005; Kim and Tsien, 2008; Kwon and Sabatini, 2011; McAllister et al., 1996; McKinney, 2010; Mitra et al., 2011; Richards et al., 2005; Thiagarajan et…”

“Studies using in vivo sensory deprivation (Maffei and Turrigiano, 2008), organotypic slice culture (Buckby et al., 2006; Karmarkar and Buonomano, 2006; Kim and Tsien, 2008), and computational modeling (Frohlich et al., 2008) have begun to explore the network effects of homeostasis.”

“268 Increase in intrinsic excitability in response to chronic activity suppression 269 In addition to synaptic homeostatic mechanisms, modulation of intrinsic excitability is an 270 important facet of neuronal adaptation (Desai et al., 1999; Kim and Tsien, 2008; Maffei and 271 Turrigiano, 2008).”

“Interestingly, feedforward and recurrent networks may exhibit fundamentally different forms of homoeostatic plasticity; Kim and Tsien (2008) reportedthatwhile inactivity increases the strength of CA3 3 CA1 (feedforward) synapses, the same was not true in CA3 3 CA3 (recurrent) synapses.”

“On a subcellular level, there are reports of homeostatic control of local dendritic regions and synapse-specific forms ofHSP (Sutton et al., 2006; Kim and Tsien, 2008; Beique et al., 2011; Petrus et al., 2015; Barnes et al., 2017).”

“…activity (Lin et al., 2008; Ramamoorthi et al., 2011), and MF-CA3 synapses are very sensitive to changes in the levels of neuronal activity (Kim and Tsien, 2008; Lee et al., 2013), we wondered whether Npas4 is involved in homeostatic shrinkage of TEs in response to neuronal activity within…”

“Indeed, clear disparities in responsiveness to chronic tetrodotoxin (TTX) treatment have been found at feedforward and recurrent excitatory synapses in hippocampu”

“…exhibited a robust increase in the amplitude (CTL: 16.51 0.98 pA, n 35 cells; TTX: 22.50 0.74 pA, n 33 cells; p 0.01; Tyler and Pozzo-Miller, 2003; Kim and Tsien, 2008; Arendt et al., 2013) and frequency of AMPARmediated mEPSCs (CTL: 0.20 0.03 Hz; TTX: 0.36 0.06 Hz; p 0.01) as determined by…”

“When the loss of input is physiological, neurons can compensate homeostatically by scaling up the strength of weakened synapses (Desai et al., 2002; Turrigiano, 1998; Kim and Tsien, 2008; Stellwagen and Malenka, 2006; Knogler et al., 2010; Goel and Lee, 2007; O’Brien et al., 1998).”

“In addition, global blockade of neuronal activity by TTX can target specific sets of synapses in an intact network to produce input-specific homeostatic changes (Kim and Tsien, 2008).”

“On the other hand, findings of tight coordination between closely neighboring synapses (18) and of differential regulation of different types of synapses (19) would be compatible with a synapse-based organization.”

“For example, in response to chronic inactivity, throughput circuits such as dentate gyrus (DG)-CA3 and CA3-CA1 scale up post-synaptic excitatory strength, while in the recurrent CA3-CA3 circuit, excitatory strength scales down (Kim and Tsien, 2008).”

“To answer this question, we chronically treated cultured hippocampal slices with TTX or bicuculline to suppress or elevate neuronal activity, respectively (Kim and Tsien, 2008; Turrigiano, 2008).”

“At this point, it is not known whether the non-multiplicative synaptic scaling of cortical neurons in vivo is due to changes in activity of speci fi c inputs, but there is evidence of input-speci fi c synaptic scaling from in vitro studies (Beique et al., 2011; Kim and Tsien, 2008; Lee et al., 2013).”

“S) Effects of DCG-IV on mEPSCs recorded from CA3 pyramidal cells in slice (N) Representative traces of mEPSC events recorded from CA3 pyramidal cells application of 2 mM DCG-IV.”

“It remains to be shown, however, whether this ability of granule cells to scale their excitatory postsynapses in a layer-specific fashion is a property of the target cell or afferent-specific, as has been shown by the group of Tsien [19,23] for the CA3 region of the hippocampus.”

“APD is generally prolonged by inactivity (Kim and Tsien, 2008; Trasande and Ramirez, 2007), an appropriate response to home-ostatically restore Ca 2+ entry, but remarkably little is known about underlying mechanisms.”

“ments in the hippocampus both pre- an postsynaptic expression was observed, while some CA3-CA3 98 connections were unexpectedly reduced after activity deprivation, other connections strengthened 99 as expected, perhaps to prevent network instability [57].”

“Proc Natl Acad Sci USA 109(40):E2726–E2734.”

“Homeostatic increases in excitability might elevate the chance of epileptic activity, or network destabilization [7,31,32].”

“Within the hippocampal trisynaptic circuit, CA3 “throughput” synapses were upregulated in response to inactivity, while recurrent synapses were downregulated [54].”

“In line with previous work (e.g., Turrigiano et al., 1998; Echegoyen et al., 2007; Kim and Tsien, 2008; Vlachos et al., 2013; Strehl et al., 2018), a homeostatic increase in excitatory synaptic strength (i.”

“…in other testing conditions in which local homeostatic responses have been reported (Sutton et al., 2006; Branco et al., 2008; Hou et al., 2008; Kim and Tsien, 2008; Deeg and Aizenman, 2011; Mitra et al., 2012) remains unknown at present and may depend on the particular experimental approach,…”

“, 2005), chronic tetrodotoxin (TTX) treatment leads to decreased EPSC frequency at hippocampal CA3 recurrent synapses (Kim and Tsien, 2008), blocking activity in layer 5 cortical interneurons with TTX enhances pyramidal cell dendritic responses (Murayama et al.”

“…that homeostatic synaptic plasticity can occur locally involving some but not all synapses of a neuron (Branco et al., 2008; Hou et al., 2008; Kim and Tsien, 2008; Lee et al., 2013; Mitra et al., 2012; Sutton et al., 2006), it is interesting to speculate that the ‘homeostatic…”

“Furthermore, solid evidence suggests that homeostatic synaptic adaptation can occur locally, in subsets of synapses (e.g., Desai et al., 2002; Kim and Tsien, 2008; Vlachos et al., 2013).”

“More recent studies have begun to address similar regulation in acute and cultured brain slices (Sutton et al., 2006; Aoto et al., 2008; Kim and Tsien, 2008; Seeburg and Sheng, 2008).”

“…on multiple spatial and temporal scales depending on activity perturbation paradigm, cell type, or developmental stage (Thiagarajan et al , 2005; Wierenga et al , 2006; Goel & Lee, 2007; Kim & Tsien, 2008; Lee et al , 2013, 2014; Lippi et al , 2016; Lee & Kirkwood, 2019; Letellier et al , 2019).”

“…plasticity can operate within autonomous subcellular compartments, and down to single synapses (Thiagarajan et al., 2005; Sutton et al., 2006; Echegoyen et al., 2007; Aoto et al., 2008; Branco et al., 2008; Kim and Tsien, 2008; Maghsoodi et al., 2008; Beique et al., 2011; Wang et al., 2019).”

“…mechanisms, leads to enhanced responses in the CA3-CA1 pathway in the absence of input to the hippocampus (Echegoyen et al., 2007; Kim and Tsien, 2008); post-lesion sprouting (Ramirez et al., 1996); and potentiation of AMPA receptor-dependent synaptic transmission and increased…”

“Silencing a cortical culture network for 2 days upregulates synaptic excitability and an increase in network activity down-regulates excitatory synaptic efficacy (Turrigiano et al., 1998; Watt et al., 2000; Murthy et al., 2001), but not all connections (Kim and Tsien, 2008).”

“It is possible that these neurons undergo adaptations and achieve synaptic homeostasis (Kim and Tsien, 2008; Macleod and Zinsmaier, 2006).”

“Input-specific homeostatic synaptic plasticity has also been observed in the hippocampus where inactivity scales up excitatory synaptic transmission in feedforward synapses while decreasing mEPSC frequency in recurrent synapses within CA3 (Kim and Tsien, 2008).”

“From the present and previous [19] studies, it is plausible to reveal upscaling of mEPSCs in the CA1 and dentate gyrus principal cells after enzymatic removal of hippocampal HSHSs in vivo as well as in Ext1-deficient mice.”

“However, recent experimental results show that synaptic scaling is observed in some situations but not in others (Goel & Lee, 2007 ; Turrigiano, 2007 ; Kim & Tsien, 2008 ).”

“…cortical neurons after an artificially induced decrease in activity (e.g. by blocking sodium channels (TTX) or glutamatergic synapses or AMPAR) (Lissin et al., 1998; O’Brien et al., 1998; Turrigiano et al., 1998; Watt et al., 2000; Thiagarajan et al., 2005; Ibata et al., 2008; Kim & Tsien, 2008).”

“Kim and Tsien (2008) showed that in CA3-to-CA3 recurrent collaterals, postsynaptic silencing overrides the presynaptic increase in release probability, leading to a significant decrease in mEPSC frequency at these synapses.”

“For example, RA is a candidate retrograde messenger at hippocampal synapses where adaptation to inactivity involves clear presynaptic modifications, such as the mossy fiberCA3 synapse (Kim and Tsien, 2008).”

“…2006; Goel and Lee, 2008; Ibata et al., 2008); however, it remains unclear whether this happens in other neuron types (Rutherford et al., 1997; Kim and Tsien, 2009), as does the extent to which homeostatic presynaptic changes in glutamate release and protein expression occur (Erickson et al.,…”

“Similar decreases in membrane excitability have also been observed in hippocampal cultures after increases in presynaptic activity and chronic depolarization (Kim & Tsien, 2008; O'Leary et al., 2010).”

“In hippocampal slice cultures, chronic TTX treatment produces synaptic strength changes not only at DG/CA3 synapses but also at CA3/CA1 and recurrent CA3 synapses (Kim and Tsien, 2008).”

“We then allowed networks to evolve under both firing rate homeostasis and spiking timing-dependent plasticity, which are evidenced by the synaptic reorganization among HVC neurons shown by our patch clamp results 31,68–70 .”

“In living systems, synapse-specific gain inhibition could be achieved by homeostatic mechanisms that dampen network reverberation, as evidenced in CA3 pyramidal cells (Kim and Tsien, 2008).”

“Growing evidence suggests that metabolic energy may be a unifying principle governing neuronal activities (Laughlin, 2001; Niven and Laughlin, 2008; Hasenstaub et al., 2010; Yu and Yu, 2017), thereby naturally leading people to focus on the relationship between metabolic energy and synaptic…”

“However, studies in more intact circuitry have demonstrated that homeostatic plasticity can be induced in an inputspecific manner (Kim and Tsien, 2008; Beique et al., 2011; Petrus et al., 2015; Chokshi et al., 2019), which suggests that postsynaptic firing rate may not be the factor that drives…”

“, 1998)), substantial evidence supports the notion that homeostatic synaptic plasticity can occur locally in specific sets of synapses (Kim and Tsien, 2008; Vlachos et al., 2013; Lenz et al., 2019).”

“Silencing a cortical culture network for two days up-regulates synaptic excitability, while an increase in activity down-regulates excitatory synaptic efficacy(Murthy et al., 2001; Turrigiano et al., 1998; Watt et al., 2000), but not all connections(Kim and Tsien, 2008).”