Exploring the Role of Camkiv in Homeostatic Plasticity

11520 • The Journal of Neuroscience, November 29, 2017 • 37(48):11520–11522

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Exploring the Role of CaMKIV in Homeostatic Plasticity

X Julia Bleier and Alexis Toliver Department of Neuroscience, Brown University, Providence, Rhode Island 02912 Review of Joseph and Turrigiano

Neural circuits must be able to appropri- in expression and distribution of voltage- tic strength, these studies used manipula- ately react to chronic changes in activity to gated ion channels and affect the likeli- tions that were not limited to the nucleus prevent excessive or insufficient activity. hood that a neuron will produce an action (Ibata et al., 2008; Pratt et al., 2011). To Hyperactivity and hypoactivity are impli- potential in response to synaptic input of rule out the possibility that regulation of cated in a wide range of neurological dis- a given strength. Although these mecha- excitatory synaptic strength is mediated orders, including epilepsy, schizophrenia, nisms have been well characterized at the by CaMKIV in the cytoplasm, where it is and Fragile X syndrome (Wondolowski cellular level, the specific molecular path- initially activated, Joseph and Turrigiano and Dickman, 2013). In the absence of ways that govern homeostatic plasticity (2017) used a nuclear localization signal other methods of regulating firing rates, are less well known. A recent study by Jo- to target CaMKIV constructs to the nucleus. activity-dependent mechanisms of Heb- seph and Turrigiano (2017) takes a closer They confirmed that the nuclear-localized bian synaptic plasticity, LTP and LTD, look at these mechanisms by investigating constitutively active form increased activa- would tend to drive neurons toward their the upstream signaling pathways that gov- tion of CREB and the nuclear-localized maximum firing rates or to silence. Previ- ern synaptic scaling and intrinsic plasticity. dominant-negative form reduced activation ous studies have shown that homeostatic Recent work has shown that calcium/ of CREB. Using whole-cell voltage-clamp mechanisms, including global synaptic calmodulin-dependent protein kinase type IV recordings of neurons transfected with the scaling and regulation of intrinsic excit- (CaMKIV), which is activated by calcium constructs, the authors measured AMPA- ability, are used to keep neurons firing in influx and initiates transcription by acti- mediated mEPSCs while blocking synaptic the middle of their dynamic range (Desai vating CREB, is involved in excitatory release, network activity, and mIPSCs. They et al., 1999; Turrigiano and Nelson, 2004; synaptic scaling (Ibata et al., 2008; Pratt et found that the amplitude of mEPSCs was Watt and Desai, 2010). Synaptic scaling is al., 2011), consistent with computational greater than controls in dnCaMKIV-expre- the process through which total synaptic models that suggest that calcium triggers ssing neurons and smaller in caCaMKIV- strength of a neuron is increased follow- synaptic scaling (Turrigiano, 2008). Given expressing neurons. As expression of these ing prolonged postsynaptic activity blo- the established cooperation between ho- constructs did not affect passive properties ckade or decreased following periods of meostatic plasticity mechanisms (Pratt or firing frequencies, the authors conclude increased activity. Whereas LTP and LTD and Aizenman, 2007; Lambo and Turri- that, as expected, nuclear CaMKIV activity are input-specific, synaptic scaling typi- cally affects a broad range of synapses by giano, 2013; Cannon and Miller, 2016), modulates excitatory synaptic strength. upregulating or downregulating expression Joseph and Turrigiano (2017) asked To determine whether CaMKIV signal- of AMPA receptors. Homeostatic regula- whether CaMKIV signaling also regulates ing has the opposite effect on inhibition, the tion of intrinsic excitability describes the inhibitory synaptic scaling and intrinsic authors measured mIPSC amplitude. Using nonsynaptic changes in a neuron’s electrical excitability. To do so, they transfected cul- whole-cell voltage-clamp recordings of trans- properties, which occur through alterations tured neocortical pyramidal neurons with fected neurons with blocked synaptic trans- either a kinase-dead, unphosphorylatable, mission, network activity, and mEPSCs, dominant-negative CaMKIV construct or they found no significant differences in Received Sept. 6, 2017; revised Oct. 20, 2017; accepted Oct. 24, 2017. a constitutively active CaMKIV construct mIPSC amplitude in neurons expressing The authors declare no competing financial interests. to reduce and increase, respectively, different constructs. The authors conclude Correspondence should be addressed to Julia Bleier, 69 Brown Street, CaMKIV activity. that cell-autonomous changes in CaMKIV Box 6873, Providence, RI 02912. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.2599-17.2017 Although previous work had shown are not responsible for regulation of inhibi- Copyright © 2017 the authors 0270-6474/17/3711520-03$15.00/0 that CaMKIV regulates excitatory synap- tory synaptic strength and that there must Bleier and Toliver • Journal Club J. Neurosci., November 29, 2017 • 37(48):11520–11522 • 11521 therefore exist another upstream signaling In contrast, in excitatory neurons, basal valuable insight regarding the degree of mechanism with this function. CaMKIV levels are much higher, allowing coordination in the upstream mecha- However, using dominant-negative and CREB activation to proceed linearly nisms of excitatory and inhibitory scaling constitutively active constructs may ob- (Cohen et al., 2016). Moreover, while in achieving the shared goal of homeo- scure the full picture when dealing with a CaMKIV activates CREB by phosphory- static plasticity. pathway that is coupled to the dynamic lating it at Ser-133, CaMKII additionally Taken together, the results of the study and tightly regulated nuclear calcium phosphorylates CREB at an inhibitory by Joseph and Turrigiano (2017) signifi- signal. Although pCREB intensity in dn- site, Ser-142, blocking its activation by cantly contribute to our knowledge of the CaMKIV neurons was significantly lower Ser-133 phosphorylation (Sun et al., 1994; upstream pathways that regulate tran- than in controls, it is possible that inhibi- Corcoran and Means, 2001; Wu and Mc- scription in homeostatic plasticity. This is tory scaling can still operate with very low Murray, 2001). In inhibitory interneu- critical to understanding how neural networks levels of CaMKIV (and pCREB). In addi- rons, which have very low levels of maintain relatively stable firing rates despite tion to measuring pCREB levels, it would CaMKII, this block would not occur. significant activity-dependent changes. be useful to measure general and active Another main goal of the study by Although excitatory synaptic scaling and CaMKIV levels with CaMKIV and anti- Joseph and Turrigiano (2017) was to intrinsic plasticity operate with different pT196 CaMKIV antibodies. Furthermore, determine whether the same upstream proximate mechanisms, they work together although this experiment shows that CaMKIV pathways regulate intrinsic plasticity and to regulate neural activity in response to signaling is insufficient to induce scaling synaptic scaling. To determine whether chronic changes. This study reinforces the at inhibitory synapses by itself, it remains CaMKIV regulates intrinsic excitability as mechanistic relationship between excitatory possible that CaMKIV signaling is neces- well as excitatory synaptic scaling, the synaptic scaling and intrinsic plasticity by sary in combination with other processes authors blocked synaptic transmission in showing that they also share a reliance on to induce scaling. Attempting to induce each type of transfected neurons and mea- the upstream CaMKIV signaling pathway. inhibitory synaptic scaling using pharma- sured firing frequency induced by various Establishing this connection invites future cological agents, such as tetrodotoxin and current steps. They found that dnCaMKIV- study of molecular factors that are known bicuculline methobromide, which respec- expressing neurons exhibited increased to activate or be activated by CaMKIV, tively, decrease and increase global activ- firing rates and caCaMKIV-expressing further elaborating these mechanisms. ity, in neurons with negligible CaMKIV neurons exhibited decreased firing rates, This work paves the way for future stud- levels, could be used to determine whether suggesting that intrinsic excitability, such ies, which will further clarify the specific nuclear CaMKIV signaling is a key as excitatory synaptic scaling, is bidirec- role of CaMKIV and other kinases in ho- player in inhibitory synaptic scaling. If tionally regulated by CaMKIV signaling. meostatic plasticity mechanisms in both the authors’ conclusion is true, these ma- Given the corresponding CaMKIV-regu- excitatory and inhibitory neurons. nipulations, which normally modulate in- lated changes in intrinsic excitability and hibitory synaptic scaling, should not show excitatory but not inhibitory synaptic References this effect. scaling, Joseph and Turrigiano (2017) Cannon J, Miller P (2016) Synaptic and intrinsic homeostasis cooperate to optimize single neu- As Joseph and Turrigiano (2017) men- predicted, and found, that CaMKIV sig- ron response properties and tune integrator tion, whether previous studies achieved naling influences basal firing rates; neu- circuits. J Neurophysiol 116:2004–2022. CrossRef cell-autonomous inhibitory synaptic scal- rons expressing dnCaMKIV exhibited Medline ing depended highly on the particular increased spontaneous firing rates and Cohen SM, Ma H, Kuchibhotla KV, Watson BO, experimental setup and manipulations neurons expressing caCaMKIV exhibited Buzsa´ki G, Froemke RC, Tsien RW (2016) (Hartman et al., 2006; Peng et al., 2010; decreased spontaneous firing rates. Excitation-transcription coupling in parval- Xue et al., 2014). In this regard, the au- The confluence of evidence from Joseph bumin-positive interneurons employs a novel CaM kinase-dependent pathway distinct from thors’ decision to perform these experi- and Turrigiano (2017) and other recent excitatory neurons. Neuron 90:292–307. CrossRef ments in excitatory pyramidal neurons studies that have investigated CaMKII and Medline could be key to their findings. Inhibitory CaMKIV signaling in excitatory neurons Corcoran EE, Means AR (2001) Defining Ca 2ϩ/ interneurons also exhibit evidence of and inhibitory interneurons suggests that calmodulin-dependent protein kinase cascades homeostatic regulation, such as activity- homeostatic regulation of excitation and in transcriptional regulation. J Biol Chem 276: dependent regulation of intrinsic prop- inhibition may be closely tied to the levels 2975–2978. CrossRef Medline Desai NS, Rutherford LC, Turrigiano GG (1999) erties (Gibson et al. 2006). Excitatory of the two kinases. It is possible that Plasticity in the intrinsic excitability of cortical synapses in neocortical excitatory neurons CaMKIV and CaMKII mediate inhibitory pyramidal neurons. Nat Neurosci 2:515–520. and inhibitory interneurons have been synaptic scaling in concert in excitatory CrossRef Medline shown to respond oppositely to brain- neurons, given that the additional phos- Gibson JR, Bartley AF, Huber KM (2006) Role derived neurotrophic factor, which medi- phorylation of Ser-142 by CaMKII might for the subthreshold currents ILeak and IH in ates synaptic scaling in response to activity cause the CREB activation curve to be- the homeostatic control of excitability in neocortical somatostatin-positive inhibitory blockade (Rutherford et al., 1998). In ad- come more similar to what is observed in neurons. J Neurophysiol 96:420–432. CrossRef dition, the two types of neurons have inhibitory neurons. Manipulating CaMKII in Medline starkly different CaMKIV levels and in- conjunction with CaMKIV or monitoring Hartman KN, Pal SK, Burrone J, Murthy VN hibitory neurons are deficient in CaMKII. P-Ser-142 in response to intracellular cal- (2006) Activity-dependent regulation of in- In inhibitory neurons, CaMKIV is a rate- cium release while attempting to evoke inhibitory synaptic transmission in hippocam- limiting factor in CREB phosphorylation hibitory scaling could help reveal whether pal neurons. Nat Neurosci 9:642–649. CrossRef because its low endogenous levels of and how these kinases work together to Medline Ibata K, Sun Q, Turrigiano GG (2008) Rapid CaMKIV tightly regulate CREB phos- achieve synaptic scaling. Performing ex- synaptic scaling induced by changes in post- phorylation, rapidly switching from periments similar to those in this study synaptic firing. Neuron 57:819–826. CrossRef minimal to maximal activation of CREB. in inhibitory neurons could also provide Medline 11522 • J. Neurosci., November 29, 2017 • 37(48):11520–11522 Bleier and Toliver • Journal Club

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