The neurobiology of insulin-like growth factor I: From neuroprotection to modulation of brain states.

After decades of research in the neurobiology of IGF-I, its role as a prototypical neurotrophic factor is undisputed. However, many of its actions in the adult brain indicate that this growth factor is not only involved in brain development or in the response to injury. Following a three-layer assessment of its role in the central nervous system, we consider that at the cellular level, IGF-I is indeed a bona fide neurotrophic factor, modulating along ontogeny the generation and function of all the major types of brain cells, contributing to sculpt brain architecture and adaptive responses to damage. At the circuit level, IGF-I modulates neuronal excitability and synaptic plasticity at multiple sites, whereas at the system level, IGF-I intervenes in energy allocation, proteostasis, circadian cycles, mood, and cognition. Local and peripheral sources of brain IGF-I input contribute to a spatially restricted, compartmentalized, and timed modulation of brain activity. To better define these variety of actions, we consider IGF-I a modulator of brain states. This definition aims to reconcile all aspects of IGF-I neurobiology, and may provide a new conceptual framework in the design of future research on the actions of this multitasking neuromodulator in the brain.

Muscarinic Receptors, from Synaptic Plasticity to its Role in Network Activity.

Acetylcholine acting via metabotropic receptors plays a key role in learning and memory by regulating synaptic plasticity and circuit activity. However, a recent overall view of the effects of muscarinic acetylcholine receptors (mAChRs) on excitatory and inhibitory long-term synaptic plasticity and on circuit activity is lacking. This review focusses on specific aspects of the regulation of synaptic plasticity and circuit activity by mAChRs in the hippocampus and cortex. Acetylcholine increases the excitability of pyramidal neurons, facilitating the generation of dendritic Ca2+-spikes, NMDA-spikes and action potential bursts which provide the main source of Ca2+ influx necessary to induce synaptic plasticity. The activation of mAChRs induced Ca2+ release from intracellular IP3-sensitive stores is a major player in the induction of a NMDA independent long-term potentiation (LTP) caused by an increased expression of AMPA receptors in hippocampal pyramidal neuron dendritic spines. In the neocortex, activation of mAChRs also induces a long-term enhancement of excitatory postsynaptic currents. In addition to effects on excitatory synapses, a single brief activation of mAChRs together with short repeated membrane depolarization can induce a long-term enhancement of GABA A type (GABAA) inhibition through an increased expression of GABAA receptors in hippocampal pyramidal neurons. By contrast, a long term depression of GABAA inhibition (iLTD) is induced by muscarinic receptor activation in the absence of postsynaptic depolarizations. This iLTD is caused by an endocannabinoid-mediated presynaptic inhibition that reduces the GABA release probability at the terminals of inhibitory interneurons. This bidirectional long-term plasticity of inhibition may dynamically regulate the excitatory/inhibitory balance depending on the quiescent or active state of the postsynaptic pyramidal neurons. Therefore, acetylcholine can induce varied effects on neuronal activity and circuit behavior that can enhance sensory detection and processing through the modification of circuit activity leading to learning, memory and behavior.

Presynaptic muscarinic control of glutamatergic synaptic transmission.

The hippocampus receives cholinergic projections from the medial septal nucleus and Broca's diagonal band that terminate in the CA1, CA3, and dentate gyrus regions (Frotscher and Leranth, 1985). Glutamatergic synapses between CA3 and CA1 pyramidal neurons are presynaptically inhibited by acetylcholine (ACh), via activation of muscarinic ACh receptors (mAChRs) at the terminals of Schaffer collaterals (SCs) (Hounsgaard, 1978; Fernández de Sevilla et al., 2002, 2003). There are two types of SC-CA1 pyramidal neuron synapses. One type, called functional synapse, shows postsynaptic alpha- amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-receptor mediated currents at resting potential (Vm) and both AMPA and N-methyl-D-aspartate receptor (NMDAR)-mediated currents when depolarized. The other type, termed silent synapse, only displays postsynaptic NMDAR-mediated currents at depolarized Vms, but does not respond at the resting Vm (Isaac et al., 1995). Using hippocampal slices obtained from young Wistar rats, we examined the effects of activation of cholinergic afferents at the stratum oriens/alveus on excitatory postsynaptic currents (EPSCs) evoked in CA1 pyramidal neurons by stimulation of SCs. We also tested the action of the nonhydrolyzable cholinergic agonist carbamylcholine chloride (CCh) on EPSCs evoked by minimal stimulation of SCs (which activates a single or very few synapses) in functional and silent synapses.

Voltage-clamp analysis of the potentiation of the slow Ca2+-activated K+ current in hippocampal pyramidal neurons.

Exploring the principles that govern activity-dependent changes in excitability is an essential step to understand the function of the nervous system, because they act as a general postsynaptic control mechanism that modulates the flow of synaptic signals. We show an activity-dependent potentiation of the slow Ca2+-activated K+ current (sl(AHP)) which induces sustained decreases in the excitability in CA1 pyramidal neurons. We analyzed the sl(AHP) using the slice technique and voltage-clamp recordings with sharp or patch-electrodes. Using sharp electrodes-repeated activation with depolarizing pulses evoked a prolonged (8-min) potentiation of the amplitude (171%) and duration (208%) of the sl(AHP). Using patch electrodes, early after entering the whole-cell configuration (<20 min), responses were as those reported above. However, although the sl(AHP) remained unchanged, its potentiation was markedly reduced in later recordings, suggesting that the underlying mechanisms were rapidly eliminated by intracellular dialysis. Inhibition of L-type Ca2+ current by nifedipine (20 microM) markedly reduced the sl(AHP) (79%) and its potentiation (55%). Ryanodine (20 microM) that blocks the release of intracellular Ca2+ also reduced sl(AHP) (29%) and its potentiation (25%). The potentiation of the sl(AHP) induced a marked and prolonged (>50%; approximately equals 8 min) decrease in excitability. The results suggest that sl(AHP) is potentiated as a result of an increased intracellular Ca2+ concentration ([Ca2+]i) following activation of voltage-gated L-type Ca2+ channels, aided by the subsequent release of Ca2+ from intracellular stores. Another possibility is that repeated activation increases the Ca2+-binding capacity of the channels mediating the sl(AHP). This potentiation of the sl(AHP) could be relevant in hippocampal physiology, because the changes in excitability it causes may regulate the induction threshold of the long-term potentiation of synaptic efficacy. Moreover, the potentiation would act as a protective mechanism by reducing excitability and preventing the accumulation of intracellular Ca2+ to toxic levels when intense synaptic activation occurs.