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Although the discovery of the critical role of α-synuclein (α-syn) in the pathogenesis of Parkinson’s disease (PD) is now twenty-five years old, it still represents a milestone in PD research. Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, α-syn-dependent early synaptic and plastic alterations and the underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, the presence of early inflammation in experimental models and PD patients, occurring before deposition and spreading of α-syn, suggests a mechanistic link between inflammation and synaptic dysfunction. The knowledge of these early mechanisms is of seminal importance to support the research on reliable biomarkers to precociously identify the disease and possible disease-modifying therapies targeting α-syn. In this review, we will discuss these critical issues, providing a state of the art of the role of this protein in early PD and other synucleinopathies.

During learning, the brain modifies synapses to improve behaviour. In the cortex, synapses are embedded within multilayered networks, making it difficult to determine the effect of an individual synaptic modification on the behaviour of the system. The backpropagation algorithm solves this problem in deep artificial neural networks, but historically it has been viewed as biologically problematic. Nonetheless, recent developments in neuroscience and the successes of artificial neural networks have reinvigorated interest in whether backpropagation offers insights for understanding learning in the cortex. The backpropagation algorithm learns quickly by computing synaptic updates using feedback connections to deliver error signals. Although feedback connections are ubiquitous in the cortex, it is difficult to see how they could deliver the error signals required by strict formulations of backpropagation. Here we build on past and recent developments to argue that feedback connections may instead induce neural activities whose differences can be used to locally approximate these signals and hence drive effective learning in deep networks in the brain.The backpropagation of error (backprop) algorithm is frequently used to train deep neural networks in machine learning, but it has not been viewed as being implemented by the brain. In this Perspective, however, Lillicrap and colleagues argue that the key principles underlying backprop may indeed have a role in brain function.

The brain has an extraordinary capacity for memory storage, but how it stores new information without disrupting previously acquired memories remains unknown. Here we show that different motor learning tasks induce dendritic Ca 2+ spikes on different apical tuft branches of individual layer V pyramidal neurons in the mouse motor cortex. These task-related, branch-specific Ca 2+ spikes cause long-lasting potentiation of postsynaptic dendritic spines active at the time of spike generation. When somatostatin-expressing interneurons are inactivated, different motor tasks frequently induce Ca 2+ spikes on the same branches. On those branches, spines potentiated during one task are depotentiated when they are active seconds before Ca 2+ spikes induced by another task. Concomitantly, increased neuronal activity and performance improvement after learning one task are disrupted when another task is learned. These findings indicate that dendritic-branch-specific generation of Ca 2+ spikes is crucial for establishing long-lasting synaptic plasticity, thereby facilitating information storage associated with different learning experiences. Ca 2+ spikes are generated on different dendritic branches in the primary motor cortex of mice performing different motor learning tasks, causing long-lasting potentiation of postsynaptic dendritic spines; inactivation of a population of interneurons disrupts the spatial separation of Ca 2+ spikes and persistent dendritic spine potentiation, suggesting that the generation of Ca 2+ spikes on different dendritic branches is crucial for storing information in individual neurons. How old and new memories coexist In experiments designed to explore how the brain stores new information without disrupting older memories, Joseph Cichon and Wen-Biao Gan used calcium imaging of neurons in the motor cortex of mice performing a series of motor learning tasks. Different learned tasks triggered Ca 2+ spikes (a sign of plasticity) in non-overlapping dendrite branches, causing long-lasting potentiation of the spines found on those branches. This specific connection between task and dendrite branch was disrupted when populations of interneurons were inactivated, suggesting a role for inhibition in maintaining the separation between branches when new information is being stored in individual neurons.

The precise underpinnings of Parkinson's disease and other disorders associated with the accumulation of α-synuclein are unclear. This study shows that PrP C mediates α-synuclein-associated synaptic dysfunction and memory deficits. Blocking specific events in receptor biology rescued cognitive deficits in mice, suggesting new possibilities for intervention in synucleinopathies. Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of α-synuclein (aSyn) in intracellular inclusions known as Lewy bodies. Prefibrillar soluble aSyn oligomers, rather than larger inclusions, are currently considered to be crucial species underlying synaptic dysfunction. We identified the cellular prion protein (PrP C ) as a key mediator in aSyn-induced synaptic impairment. The aSyn-associated impairment of long-term potentiation was blocked in Prnp null mice and rescued following PrP C blockade. We found that extracellular aSyn oligomers formed a complex with PrP C that induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). aSyn engagement of PrP C and Fyn activated NMDA receptor (NMDAR) and altered calcium homeostasis. Blockade of mGluR5-evoked phosphorylation of NMDAR in aSyn transgenic mice rescued synaptic and cognitive deficits, supporting the hypothesis that a receptor-mediated mechanism, independent of pore formation and membrane leakage, is sufficient to trigger early synaptic damage induced by extracellular aSyn.

Defective brain hormonal signaling has been associated with Alzheimer’s disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD. Expression of the exercise-induced myokine irisin (FNDC5) is lower in patients with AD. Whereas knockdown of FNDC5/irisin is sufficient to induce learning and memory deficits, restoration of its expression can ameliorate these phenotypes in rodent models.

Dendritic spines are the major loci of synaptic plasticity and are considered as possible structural correlates of memory. Nonetheless, systematic manipulation of specific subsets of spines in the cortex has been unattainable, and thus, the link between spines and memory has been correlational. We developed a novel synaptic optoprobe, AS-PaRac1 (activated synapse targeting photoactivatable Rac1), that can label recently potentiated spines specifically, and induce the selective shrinkage of AS-PaRac1-containing spines. In vivo imaging of AS-PaRac1 revealed that a motor learning task induced substantial synaptic remodelling in a small subset of neurons. The acquired motor learning was disrupted by the optical shrinkage of the potentiated spines, whereas it was not affected by the identical manipulation of spines evoked by a distinct motor task in the same cortical region. Taken together, our results demonstrate that a newly acquired motor skill depends on the formation of a task-specific dense synaptic ensemble. A new light-activated probe that targets recently active neuronal spines for manipulation induces shrinkage of recently potentiated spines following a motor learning task; spine shrinkage disrupted learning, suggesting a causal relationship between the specific subset of targeted spines and the learned behaviour. Memory tracked using synaptic optogenetics It has long been speculated that changes in spine stability and potentiation are the structural correlates of memory, but tools to help link these structural changes to specific memories have not been available. Akiko Hayashi-Takagi et al . have developed a new light-activated probe that targets recently active spines for manipulation. Optically induced shrinkage of recently potentiated spines following a motor learning task is seen to disrupt learning, suggesting a causal relationship between the specific subset of targeted spines and the learned behaviour.

Key Points AMPA receptors (AMPARs) mediate nearly all fast excitatory neurotransmission in the mammalian CNS. AMPARs are heteromeric assemblies of four core subunits, GluA1–4, together with auxiliary subunits and a dynamically changing set of interacting proteins. The assembly and subunit composition of AMPARs undergo activity-dependent regulation during biogenesis. The presence or absence of the edited form of the GluA2 subunit, GluA2(R), determines whether the assembled AMPAR gates Ca 2+ . There is a wealth of evidence suggesting that the synaptic trafficking, retention and removal of AMPARs of specific subunit combinations and that have specific biophysical properties are of paramount importance for synaptic plasticity. These AMPAR-subtype-specific events are regulated both by protein interactions and by phosphorylation events within the carboxy-terminal tails. Recent studies reporting that the C-terminal tails are not essential for plasticity and that very few GluA1 subunits are phosphorylated have prompted a major re-evaluation of the fundamental mechanisms of AMPAR trafficking and synaptic plasticity. Understanding the molecular details of AMPAR assembly, trafficking, recycling and degradation, and how dysfunction affects synapses, neurons and networks will provide invaluable insights into neurological and neurodegenerative disease. AMPA receptor (AMPAR) subunit composition is thought to influence trafficking, but recent findings have challenged previously accepted models for how this might occur. In this Review, Henley and Wilkinson provide an overview of how different receptor subunits affect AMPAR assembly, trafficking and function under normal and pathological conditions. AMPA receptors (AMPARs) are assemblies of four core subunits, GluA1–4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs, and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity and in response to neuronal stress in disease. Recently, the subunit dependence of AMPAR trafficking has been questioned, leading to a reappraisal of this field. In this Review, we discuss what is known, uncertain, conjectured and unknown about the roles of the individual subunits, and how they affect AMPAR assembly, trafficking and function under both normal and pathological conditions.

Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing. A study of pup retrieval behaviour in mice shows that oxytocin modulates cortical responses to pup calls specifically in the left auditory cortex; in virgin females, call-evoked responses were enhanced, thus increasing their salience, by pairing oxytocin delivery in the left auditory cortex with the calls, suggesting enhancement was a result of balancing the magnitude and timing of inhibition with excitation. Maternal actions of oxytocin The role of oxytocin in modulating social interactions and maternal behaviour is well documented, but how this hormone influences neural circuits to drive these behavioral changes is not well understood. Here, Robert Froemke and colleagues study pup retrieval behaviour in mice and find that oxytocin modulates cortical responses to pup calls specifically in the left auditory cortex. In virgin females, call-evoked responses were enhanced, thus increasing their salience, by pairing oxytocin delivery in left auditory cortex with the calls. This enhancement came about through a specific balancing of the magnitude and timing of inhibition with excitation.

A rodent study using optogenetics to induce long-term potentiation and long-term depression provides a causal link between synaptic plasticity and memory. Memories made and unmade It has long been thought that the neural mechanisms underlying memories involve synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), but demonstrating a causal link between these synaptic processes and memory has been difficult. Now, Roberto Malinow and colleagues claim to have done just that in mice undergoing fear conditioning. The authors use optogenetics to isolate a specific fear memory circuit and then induce LTD or LTP within the circuit to remove or reinstate the memory. It has been proposed that memories are encoded by modification of synaptic strengths through cellular mechanisms such as long-term potentiation (LTP) and long-term depression (LTD) 1 . However, the causal link between these synaptic processes and memory has been difficult to demonstrate 2 . Here we show that fear conditioning 3 , 4 , 5 , 6 , 7 , 8 , a type of associative memory, can be inactivated and reactivated by LTD and LTP, respectively. We began by conditioning an animal to associate a foot shock with optogenetic stimulation of auditory inputs targeting the amygdala, a brain region known to be essential for fear conditioning 3 , 4 , 5 , 6 , 7 , 8 . Subsequent optogenetic delivery of LTD conditioning to the auditory input inactivates memory of the shock. Then subsequent optogenetic delivery of LTP conditioning to the auditory input reactivates memory of the shock. Thus, we have engineered inactivation and reactivation of a memory using LTD and LTP, supporting a causal link between these synaptic processes and memory.

Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) 1 – 3 . However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP 4 – 8 also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B 9 – 14 . Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked. Several independent lines of evidence demonstrated long-term potentiation induction by a structural function of calmodulin-dependent protein kinase II rather than by its enzymatic activity.