Translational control through the mammalian target of rapamycin (mTOR) is critical for synaptic plasticity, cell growth, and axon guidance. Recently, it was also shown that mTOR signaling was essential for the maintenance of the sensitivity of subsets of adult sensory neurons. Here, we show that persistent pain states, but not acute pain behavior, are substantially alleviated by centrally administered rapamycin, an inhibitor of the mTOR pathway. We demonstrate that rapamycin modulates nociception by acting on subsets of primary afferents and superficial dorsal horn neurons to reduce both primary afferent sensitivity and central plasticity. We found that the active form of mTOR is present in a subpopulation of myelinated dorsal root axons, but rarely in unmyelinated C-fibers, and heavily expressed in the dorsal horn by lamina I/III projection neurons that are known to mediate the induction and maintenance of pain states. Intrathecal injections of rapamycin inhibited the activation of downstream targets of mTOR in dorsal horn and dorsal roots and reduced the thermal sensitivity of A-fibers. Moreover, in vitro studies showed that rapamycin increased the electrical activation threshold of A␦-fibers in dorsal roots. Together, our results imply that central rapamycin reduces neuropathic pain by acting both on an mTOR-positive subset of A-nociceptors and lamina I projection neurons and suggest a new pharmacological route for therapeutic intervention in persistent pain states.

Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states.

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Cerebellar posterior interpositus neurons were recorded in cats during delayed and trace conditioning of eyeblinks. Type A neurons increased their firing in the time interval between conditioned and unconditioned stimulus presentations for both paradigms, while type B neurons decreased it. The discharge of different type A neurons recorded across successive conditioning sessions increased, with slopes of 0.061-0.078 spikes/s/trial. Both types of neurons modified their firing several trials in advance of the appearance of eyelid conditioned responses, but for each conditioned stimulus presentation their response started after conditioned response onset. Interpositus microstimulation evoked eyelid responses similar in amplitude and profiles to conditioned responses, and microinjection of muscimol decreased conditioned response amplitude. It is proposed that the interpositus nucleus is an enhancer, but not the initiator, of eyelid conditioned responses.

The role of cerebellar circuits in the acquisition of new motor abilities is still a matter of intensive debate. To establish the contribution of posterior interpositus nucleus (PIN) to the performance and/or acquisition of reflex and classically conditioned responses (CRs) of the eyelid, the effects of microstimulation and/or pharmacological inhibition by muscimol of the nucleus were investigated in conscious cats. Microstimulation of the PIN in naive animals evoked ramp-like eyelid responses with a wavy appearance, without producing any noticeable plastic functional change in the cerebellar and brainstem circuits involved. Muscimol microinjections decreased the amplitude of reflex eyeblinks evoked by air puffs, both when presented alone or when paired with a tone as conditioned stimulus (CS). In half-conditioned animals, muscimol injections also decreased the amplitude and damped the typical wavy profile of CRs, whereas microstimulation of the same sites increased both parameters. However, neither muscimol injections nor microstimulation modified the expected percentage of CRs, suggesting a major role of the PIN in the performance of eyelid responses rather than in the learning process. Moreover, the simultaneous presentation of CS and microstimulation in well trained animals evoked CRs similar in amplitude to the added value of those evoked by the two stimuli presented separately. In contrast, muscimol-injected animals developed CRs to paired CS and microstimulation presentations, larger than those evoked by the two stimuli when presented alone. It is concluded that the PIN contributes to the enhancement of both reflex and conditioned eyelid responses and to the damping of resonant properties of neuromuscular elements controlling eyelid kinematics.

The hippocampus plays a critical role in learning and memory. Its correct performance relies on excitatory/inhibitory synaptic transmission balance. In early stages of Alzheimer’s disease (AD), neuronal hyperexcitability leads to network dysfunction observed in cortical regions such as the hippocampus. G-protein-gated potassium (GirK) channels induce neurons to hyperpolarize, contribute to the resting membrane potential and could compensate any excesses of excitation. Here, we have studied the relationship between GirK channels and hippocampal function in a mouse model of early AD pathology. Intracerebroventricular injections of amyloid-β (Aβ 1-42) peptide—which have a causal role in AD pathogenesis—were performed to evaluate CA3–CA1 hippocampal synapse functionality in behaving mice. Aβ increased the excitability of the CA3–CA1 synapse, impaired long-term potentiation (LTP) and hippocampal oscillatory activity, and induced deficits in novel object recognition (NOR) tests. Injection of ML297 alone, a selective GirK activator, was also translated in LTP and NOR deficits. However, increasing GirK activity rescued all hippocampal deficits induced by Aβ due to the restoration of excitability values in the CA3–CA1 synapse. Our results show a synaptic mechanism, through GirK channel modulation, for the prevention of the hyperexcitability that causally contributes to synaptic, network, and cognitive deficits found in early AD pathogenesis.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, brain atrophy due to neuronal and synapse loss, and formation of two pathological lesions: extracellular amyloid plaques, composed largely of amyloid-beta peptide (Aβ), and neurofibrillary tangles formed by intracellular aggregates of hyperphosphorylated tau protein. Lesions mainly accumulate in brain regions that modulate cognitive functions such as the hippocampus, septum or amygdala. These brain structures have dense reciprocal glutamatergic, cholinergic, and GABAergic connections and their relationships directly affect learning and memory processes, so they have been proposed as highly susceptible regions to suffer damage by Aβ during AD course. Last findings support the emerging concept that soluble Aβ peptides, inducing an initial stage of synaptic dysfunction which probably starts 20–30 years before the clinical onset of AD, can perturb the excitatory–inhibitory balance of neural circuitries. In turn, neurotransmission imbalance will result in altered network activity that might be responsible of cognitive deficits in AD. Therefore, Aβ interactions on neurotransmission systems in memory-related brain regions such as amygdaloid complex, medial septum or hippocampus are critical in cognitive functions and appear as a pivotal target for drug design to improve learning and dysfunctions that manifest with age. Since treatments based on glutamatergic and cholinergic pharmacology in AD have shown limited success, therapies combining modulators of different neurotransmission systems including recent findings regarding the GABAergic system, emerge as a more useful tool for the treatment, and overall prevention, of this dementia. In this review, focused on inhibitory systems, we will analyze pharmacological strategies to compensate neurotransmission imbalance that might be considered as potential therapeutic interventions in AD.

Last evidences suggest that, in Alzheimer's disease (AD) early stage, Amyloid-β (Aβ) peptide induces an imbalance between excitatory and inhibitory neurotransmission systems resulting in the functional impairment of neural networks. Such alterations are particularly important in the septohippocampal system where learning and memory processes take place depending on accurate oscillatory activity tuned at fimbria-CA3 synapse. Here, the acute effects of Aβ on CA3 pyramidal neurons and their synaptic activation from septal part of the fimbria were studied in rats. A triphasic postsynaptic response defined by an excitatory potential (EPSP) followed by both early and late inhibitory potentials (IPSP) was evoked. The EPSP was glutamatergic acting on ionotropic receptors. The early IPSP was blocked by GABAA antagonists whereas the late IPSP was removed by GABAB antagonists. Aβ perfusion induced recorded cells to depolarize, increase their input resistance and decrease the late IPSP. Aβ action mechanism was localized at postsynaptic level and most likely linked to GABAB-related ion channels conductance decrease. In addition, it was found that the specific pharmacological modulation of the GABAB receptor effector, G-protein-coupled inward rectifier potassium (GirK) channels, mimicked all Aβ effects previously described. Thus, our findings suggest that Aβ altering GirK channels conductance in CA3 pyramidal neurons might have a key role in the septohippocampal activity dysfunction observed in AD.