Correlated network activity enhances synaptic efficacy via BDNF and the ERK pathway at immature CA3–CA1 connections in the hippocampus

Abstract

At early developmental stages, correlated neuronal activity is thought to exert a critical control on functional and structural refinement of synaptic connections. In the hippocampus, between postnatal day 2 (P2) and P6, network-driven giant depolarizing potentials (GDPs) are generated by the synergistic action of glutamate and GABA, which is depolarizing and excitatory. Here the rising phase of GDPs was used to trigger Schaffer collateral stimulation in such a way that synchronized network activity was coincident with presynaptic activation of afferent input. This procedure produced a persistent increase in spontaneous and evoked ␣-amino-3-hydroxy-5-methyl-4-isoxadepropionic acid-mediated glutamatergic currents, an effect that required calcium influx through postsynaptic L-type calcium channels. No potentiation was observed when a delay of 3 sec was introduced between GDPs and afferent stimulation. Pairing-induced potentiation was prevented by scavengers of endogenous BDNF or tropomyosin-related kinase receptor B (TrkB) receptor antagonists. Blocking TrkB receptors in the postsynaptic cell did not prevent the effects of pairing, suggesting that BDNF, possibly secreted from the postsynaptic cell during GDPs, acts on TrkB receptors localized on presynaptic neurons. Application of exogenous BDNF mimicked the effects of pairing on synaptic transmission. In addition, pairing-induced synaptic potentiation was blocked by ERK inhibitors, suggesting that BDNF activates the MAPK/ERK cascade, which may lead to transcriptional regulation and new protein synthesis in the postsynaptic neuron. These results support the hypothesis that, during a critical period of postnatal development, GABA A-mediated GDPs are instrumental in tuning excitatory synaptic connections and provide insights into the molecular mechanisms involved in this process.development ͉ giant depolarizing potential ͉ excitatory postsynaptic current ͉ synaptic pairing ͉ TrkB receptors S pontaneously occurring neuronal oscillations constitute a hallmark of developmental networks (1). In the immature hippocampus, giant depolarizing potentials (GDPs) represent a primordial form of synchrony between neurons, which precedes more organized forms of activity, such as the theta and gamma rhythms (2). These events, which are characterized by recurrent membrane depolarization with superimposed fast-action potentials separated by long and variable intervals of several seconds, are generated when the synaptic traffic and cell firing within the network increase to a threshold level (3). GDPs are synaptic in origin and involve the action of both glutamate and GABA, which, during a restricted period of postnatal development, is depolarizing and excitatory (4-6). The depolarizing action of GABA during GDPs results in the activation of voltagedependent calcium channels and N-methyl-D-aspartate receptors (7). GDPs also can be recorded in vivo in rat pups, in which they occur during immobility periods, sleep, and feeding (8). GDP-associated calcium waves are thought to be crucial...

At Immature Mossy-Fiber–CA3 Synapses, Correlated Presynaptic and Postsynaptic Activity Persistently Enhances GABA Release and Network Excitability via BDNF and cAMP-Dependent PKA

“…As in other forms of developmental plasticity (Gaiarsa et al, 2002;Kasyanov et al, 2004;Mohajerani et al, 2007), calcium entering into the cell through VDCCs was responsible for positive changes in synaptic efficacy as demonstrated by the lack of STD-LTP when BAPTA was present in the recording pipette or when nifedipine was added to the extracellular solution. In accord to the calcium hypothesis, the direction of synaptic changes would be determined by distinct calcium signals which would activate different molecular pathways (Caporale and Dan, 2008).…”

“…One attractive candidate is BDNF, which can be released in a calciumdependent way by depolarization of the postsynaptic cell (Goodman et al, 1996;Lessmann et al, 2003;Magby et al, 2006;Kuczewski et al, 2008b). Previous studies from the immature hippocampus have shown that BDNF is the retrograde messenger required for increasing the probability of GABA and glutamate release at GABAergic and glutamatergic synapses, respectively (Gubellini et al, 2005;Mohajerani et al, 2007). Therefore, we tested whether BDNF was able to mimic the effects of STD-LTP on MF-evoked GPSCs.…”

NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development

“…these glutamatergic synapses (Mohajerani et al, 2007). Therefore, the observed decrease in coincident activity in Nkcc1 Ϫ/Ϫ hippocampus might change glutamatergic transmission between the Schaffer collaterals and CA1 neurons.…”

Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats

“…Neurotrophins may be key in the development of depression (13); BDNF, for instance, can activate intracellular mitogen-activated protein kinase/extracellular signal-regulated kinase cascade signaling pathways (14), affecting synaptic plasticity (12) and alleviating the symptoms of depression (15), and BDNF may thus be important in the maintenance of emotional stability. Deletion of the BDNF receptor induces a reduction in neurogenesis and increases anxious behavior (16).…”