Mammalian target of rapamycin complex 1 activation negatively regulates Polo-like kinase 2-mediated homeostatic compensation following neonatal seizures

Abstract

Homeostatic plasticity is characterized by compensatory changes in synaptic strength and intrinsic membrane properties in response to chronic changes in neuronal activity. Neonatal seizures are a naturally occurring source of neuronal overactivation and can lead to long-term epilepsy and cognitive deficits. Using a rodent model of hypoxiainduced neonatal seizures that results in a persistent increase in AMPA receptor (AMPAR) function in hippocampal CA1 pyramidal neurons, we aimed to determine whether there was any evidence of an opposing endogenous homeostatic antiepileptic response. Given that this model results in long-term epilepsy, we also examined mechanisms whereby this homeostasis fails. Whole-cell patch-clamp recordings from neurons in slices removed at intervals following seizure onset revealed an initial up-regulation of AMPAR function that was followed by a transient dynamic attenuation of this enhancement by 48-72 h, although AMPAR function was still increased compared with nonseizure control baseline. This secondary down-regulation of enhanced AMPAR function was coincident with a marked transient increase in expression and function of the Polo-like kinase 2 (PLK2), which has previously been implicated in homeostatic down-regulation of neuronal excitability in cell/slice culture models. The effects were transient and at 1 wk AMPAR function once again became up-regulated, simultaneous with a decrease in PLK2 expression and function. This negative regulation was mediated by subacute postseizure increases in mammalian target of rapamycin (mTOR). Application of the mTOR inhibitor rapamycin prevented post-hypoxic seizure impairment of homeostasis, suggesting that homeostatic plasticity mechanisms may be potentially modifiable therapeutic targets in epileptogenesis.pilepsy is one of the most prevalent neurological disorders, affecting ∼1-2% of the United States population (1). The neonatal period is one of the highest incidence periods for seizures across the lifespan, with hypoxic encephalopathy being the most common cause (2, 3). Neonatal seizures are often refractory to conventional antiepileptic drugs and can result in chronic laterlife epilepsy and long-term behavioral and cognitive deficits (4, 5).Using an established neonatal hypoxic seizure (HS) model in rats, we previously showed neonatal HS results in both acute and long-term enhancement in hippocampal and cortical excitability and later-life epilepsy (6-8). We have demonstrated a critical role for seizure-induced early posttranslational modifications of the AMPA receptors (AMPAR) to enhance synaptic excitability (3,6,7,9), and a dependence upon activation of the mammalian target of rapamycin (mTOR) pathway (9).Neonatal seizure-induced increases in AMPAR function involve mechanisms of receptor trafficking implicated in Hebbian synaptic plasticity (6, 10). Although Hebbian synaptic plasticity is robust in the developing brain at baseline and after seizures, relatively few studies have focused on the status of homeostatic plasticity in the developi...

Models of hypoxia and ischemia-induced seizures

“…Q3 There are a number of hypoxia-induced seizure models that reproduce important clinical features of HIE in the neonatal http://dx.doi.org/10.1016/j.jneumeth.2015.09.023 0165-0270/© 2015 Published by Elsevier B.V. Holtzman et al (1999) and Kekelidze et al (2000) population by brief exposure of immature rats to graded global hypoxia (Jensen et al, 1991;Moshe and Albala, 1985) (Table 1). Such hypoxia-induced seizures usually occur in a specific age window and lead to both acute and long-term network hyperexcitability, spontaneous seizures and later in life cognitive deficits without acute neuronal death (Chen et al, 2006;Jensen et al, 1991Jensen et al, , 1998Jensen and Wang, 1996;Laroia et al, 1997;Moshe and Albala, 1985;Rakhade et al, 2011Rakhade et al, , 2008Rubaj et al, 2003;Sanchez et al, 2000Sanchez et al, , 2005Sanchez and Jensen, 2001;Sato et al, 1994;Sun et al, 2013;Wais et al, 2009;Yager and Ashwal, 2009;Yang et al, 2004;Zanelli et al, 2014). In this section, we will provide an overview of the animal species used in hypoxia-induced seizure study.…”

Homeostatic Synaptic Plasticity In the Hippocampus: Therapeutic Prospects For Seizure Control?

“…These extended periods of hypoactivity would be expected to eventually induce homeostatic restrengthening of synapses in an attempt to restore network activity. Indeed, in rodent models of hypoxiainduced neonatal seizures, compensatory hippocampal synaptic strengthening has been observed in the weeks following status epilepticus and is associated with the emergence of spontaneous seizures [10]. This observation raises the possibility that homeostatic overcompensation may underlie the emergence of spontaneous recurrent seizures.…”

“…Inhibition of Plk2 activity has been associated with the emergence of spontaneous seizures following neonatal hypoxic seizures in rodents [10]. Intriguingly, Plk2 appears to be negatively regulated by the mTORC1 pathway [10], an intensely studied epileptogenic signaling cascade. Mutations of TSC1 or TSC2 upstream of mTOR cause tuberous sclerosis, in which approximately 80% of patients develop epilepsy [13].…”

“…One promising molecular target is Plk2, a protein kinase that is transcriptionally induced in response to sustained network activity and acts as a brake on excitatory synapses [12]. Inhibition of Plk2 activity has been associated with the emergence of spontaneous seizures following neonatal hypoxic seizures in rodents [10]. Intriguingly, Plk2 appears to be negatively regulated by the mTORC1 pathway [10], an intensely studied epileptogenic signaling cascade.…”

Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology

“…3), suggesting a transcription-and translation-independent mechanism. The classic slow homeostatic regulators depress AMPA responses prior to NMDA responses (Hsieh et al 2006;Rial Verde et al 2006;Seeburg et al 2008;Evers et al 2010;Sun et al 2013). On the other hand, the rapid action of Cdk5 makes it uncertain whether Cdk5 depresses AMPA responses first (Tomizawa et al 2002;Yan et al 2002;Chergui et al 2004), or suppresses NMDA responses first (Hawasli et al 2007;Plattner et al 2014).…”