Elke Edelmann

Theta Burst Firing Recruits BDNF Release and Signaling in Postsynaptic CA1 Neurons in Spike-Timing-Dependent LTP

Timing-dependent LTP (t-LTP) is a physiologically relevant type of synaptic plasticity that results from repeated sequential firing of action potentials (APs) in pre- and postsynaptic neurons. t-LTP can be observed in vivo and is proposed to be a cellular correlate of memory formation. While brain-derived neurotrophic factor (BDNF) is essential to high-frequency stimulation-induced LTP in many brain areas, the role of BDNF in t-LTP is largely unknown. Here, we demonstrate a striking change in the expression mechanism of t-LTP in CA1 of the hippocampus following two distinct modes of synaptic activation. Single postsynaptic APs paired with presynaptic stimulation activated a BDNF-independent canonical t-LTP. In contrast, a theta burst of postsynaptic APs preceded by presynaptic stimulation elicited BDNF-dependent postsynaptic t-LTP that relied on postsynaptic BDNF secretion. This suggests that BDNF release during burst-like patterns of activity typically observed in vivo may play a crucial role during memory formation.

Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus

Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain. Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear. Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/-) mice we observed impaired (∼50%) NMDAR-independent MF-LTP. In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected. To exclude that impaired MF-LTP in BDNF+/- mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling. Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/- mice. Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/- mice. Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP. Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus.

Fish inner ear otoliths stop calcium incorporation after vestibular nerve transection

Previous investigations revealed that the growth of fish inner ear otoliths (otolith size and calcium incorporation) depends on the amplitude and the direction of gravity, suggesting the existence of a (negative) feedback mechanism.In a search for the regulating unit, the vestibular nerve was unilaterally transected in neonatal swordtail fish (Xiphophorus helleri) which were subsequently incubated in the calciumtracer alizarin-complexone. Calcium incorporation and thus otolith growth ceased on the operated head sides, indicating that the brain is significantly involved in regulating otolith growth.

Dopamine regulates intrinsic excitability thereby gating successful induction of spike timing-dependent plasticity in CA1 of the hippocampus

Long-term potentiation (LTP) and long-term depression (LTD) are generally assumed to be cellular correlates for learning and memory. Different types of LTP induction protocols differing in severity of stimulation can be distinguished in CA1 of the hippocampus. To better understand signaling mechanisms and involvement of neuromodulators such as dopamine (DA) in synaptic plasticity, less severe and more physiological low frequency induction protocols should be used. In the study which is reviewed here, critical determinants of spike timing-dependent plasticity (STDP) at hippocampal CA3-CA1 synapses were investigated. We found that DA via D1 receptor signaling, but not adrenergic signaling activated by the β-adrenergic agonist isoproterenol, is important for successful expression of STDP at CA3-CA1 synapses. The DA effect on STDP is paralleled by changes in spike firing properties, thereby changing intrinsic excitability of postsynaptic CA1 neurons, and gating STDP. Whereas β-adrenergic signaling also leads to a similar (but not identical) regulation of firing pattern, it does not enable STDP. In this focused review we will discuss the current literature on dopaminergic modulation of LTP in CA1, with a special focus on timing dependent (t-)LTP, and we will suggest possible reasons for the selective gating of STDP by DA [but not noradrenaline (NA)] in CA1.

Dopamine Modulates Spike Timing-Dependent Plasticity and Action Potential Properties in CA1 Pyramidal Neurons of Acute Rat Hippocampal Slices

Spike timing-dependent plasticity (STDP) is a cellular model of Hebbian synaptic plasticity which is believed to underlie memory formation. In an attempt to establish a STDP paradigm in CA1 of acute hippocampal slices from juvenile rats (P15–20), we found that changes in excitability resulting from different slice preparation protocols correlate with the success of STDP induction. Slice preparation with sucrose containing ACSF prolonged rise time, reduced frequency adaptation, and decreased latency of action potentials in CA1 pyramidal neurons compared to preparation in conventional ASCF, while other basal electrophysiological parameters remained unaffected. Whereas we observed prominent timing-dependent long-term potentiation (t-LTP) to 171 ± 10% of controls in conventional ACSF, STDP was absent in sucrose prepared slices. This sucrose-induced STDP deficit could not be rescued by stronger STDP paradigms, applying either more pre- and/or postsynaptic stimuli, or by a higher stimulation frequency. Importantly, slice preparation with sucrose containing ACSF did not eliminate theta-burst stimulation induced LTP in CA1 in field potential recordings in our rat hippocampal slices. Application of dopamine (for 10–20 min) to sucrose prepared slices completely rescued t-LTP and recovered action potential properties back to levels observed in ACSF prepared slices. Conversely, acute inhibition of D1 receptor signaling impaired t-LTP in ACSF prepared slices. No similar restoring effect for STDP as seen with dopamine was observed in response to the β-adrenergic agonist isoproterenol. ELISA measurements demonstrated a significant reduction of endogenous dopamine levels (to 61.9 ± 6.9% of ACSF values) in sucrose prepared slices. These results suggest that dopamine signaling is involved in regulating the efficiency to elicit STDP in CA1 pyramidal neurons.

Coexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons

Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation in vivo. Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the brain. We hypothesize that resolving the subcellular location of t-LTP and t-LTD mechanisms that are regulated by distinct neuromodulator systems will be essential to reach a more cohesive understanding of synaptic plasticity in memory formation.

The expression mechanism of the residual LTP in the CA1 region of BDNF k.o. mice is insensitive to NO synthase inhibition

BDNF and nitric oxide signaling both contribute to long-term potentiation (LTP) at glutamatergic synapses, but to date, few studies analyzed the interaction of both signaling cascades in the same synaptic pathway. Here we addressed the question whether the residual LTP in the CA1 region of hippocampal slices from heterozygous BDNF knockout mice (BDNF⁺/⁻) is dependent on nitric oxide (NO) signaling. Extracellular recording of synaptic field potentials elicited by presynaptic Schaffer collateral stimulation was performed in the CA1 region of hippocampal slices of 4- to 6-week-old mice, and LTP was induced by a theta burst stimulation protocol. Application of the nitric oxide inhibitor L-NAME (200 μM) strongly inhibited LTP by 70% in wildtype animals. This inhibition of LTP was not a consequence of altered basal synaptic properties. In CA1 of BDNF⁺/⁻ mice, stimulated with the same theta burst protocol, LTP was reduced by 50% as compared to wildtype animals. This impairment in the expression of LTP in BDNF⁺/⁻ mice did not result from an increased synaptic fatigue. The residual LTP in BDNF⁺/⁻ was not further reduced by preincubation of slices with L-NAME. These results suggest that BDNF and NO share overlapping intracellular signaling cascades to mediate LTP in CA1, and part of their signaling cascades are most likely arranged consecutively in the signaling pathway mediating LTP.

Neuronal feedback between brain and inner ear for growth of otoliths in fish

Previous investigations revealed that fish inner ear otolith growth (concerning otolith size and calcium-incorporation) depends on the amplitude and the direction of gravity, suggesting the existence of a (negative) feedback mechanism. In search for the regulating unit, the vestibular nerve was unilaterally transected in neonate swordtail fish (Xiphophorus helleri) which were subsequently incubated in the calcium-tracer alizarin-complexone. Calcium incorporation ceased on the transected head sides, indicating that calcium uptake is neurally regulated.

Effects of vestibular nerve transection on the calcium incorporation of fish otoliths.

Previous investigations revealed that the growth of fish inner ear otoliths (otolith size and calcium-incorporation) depends on the amplitude and the direction of gravity, suggesting the existence of a (negative) feedback mechanism. In search for the regulating unit, the vestibular nerve was transacted unilaterally in neonate swordtail fish (Xiphophorus helleri) which were subsequently incubated in the calcium-tracer alizarin-complexone. Calcium incorporation ceased on the transacted head sides, indicating that calcium uptake is neurally regulated. Grant numbers: 50 WB 9533, 50 WB 9997.

Dopaminergic innervation and modulation of hippocampal networks

The catecholamine dopamine plays an important role in hippocampus-dependent plasticity and related learning and memory processes. Dopamine secretion in the hippocampus is activated by, e.g., salient or novel stimuli, thereby helping to establish and to stabilize hippocampus-dependent memories. Disturbed dopaminergic function in the hippocampus leads to severe pathophysiological conditions. While the role and importance of dopaminergic modulation of hippocampal networks have been unequivocally proven, there is still a lack of detailed molecular and cellular mechanistic understanding of how dopamine orchestrates these hippocampal processes. In this chapter of the special issue “Hippocampal structure and function,” we will discuss the current understanding of dopaminergic modulation of basal synaptic transmission and long-lasting, activity-dependent potentiation or depression.