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Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity is associated with compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced grooming in Sapap3-knockouts. Together, these findings highlight the striatal indirect pathway as a potential treatment target for compulsive behavior., (© 2024. The Author(s).)

Inhibitory neurons play a fundamental role in the normal operation of neuronal networks. Diverse types of inhibitory neurons serve vital functions in cortical networks, such as balancing excitation and taming excessive activity, organizing neuronal activity in spatial and temporal patterns, and shaping response selectivity. Serving these, and a multitude of other functions effectively requires fine-tuning of inhibition, mediated by synaptic plasticity. Plasticity of inhibitory systems can be mediated by changes at inhibitory synapses and/or by changes at excitatory synapses at inhibitory neurons. In this review, we consider that latter locus: plasticity at excitatory synapses to inhibitory neurons. Despite the fact that plasticity of excitatory synaptic transmission to interneurons has been studied in much less detail than in pyramids and other excitatory cells, an abundance of forms and mechanisms of plasticity have been observed in interneurons. Specific requirements and rules for induction, while exhibiting a broad diversity, could correlate with distinct sources of excitatory inputs and distinct types of inhibitory neurons. One common requirement for the induction of plasticity is the rise of intracellular calcium, which could be mediated by a variety of ligand-gated, voltage-dependent, and intrinsic mechanisms. The majority of the investigated forms of plasticity can be classified as Hebbian-type associative plasticity. Hebbian-type learning rules mediate adaptive changes of synaptic transmission. However, these rules also introduce intrinsic positive feedback on synaptic weight changes, making plastic synapses and learning networks prone to runaway dynamics. Because real inhibitory neurons do not express runaway dynamics, additional plasticity mechanisms that counteract imbalances introduced by Hebbian-type rules must exist. We argue that weight-dependent heterosynaptic plasticity has a number of characteristics that make it an ideal candidate mechanism to achieve homeostatic regulation of synaptic weight changes at excitatory synapses to inhibitory neurons., (Copyright © 2020 Bannon, Chistiakova and Volgushev.)

Photoactivatable pharmacological agents have revolutionized neuroscience, but the palette of available compounds is limited. We describe a general method for caging tertiary amines by using a stable quaternary ammonium linkage that elicits a red shift in the activation wavelength. We prepared a photoactivatable nicotine (PA-Nic), uncageable via one- or two-photon excitation, that is useful to study nicotinic acetylcholine receptors (nAChRs) in different experimental preparations and spatiotemporal scales.

Ethanol is one of the most commonly used substances in the world. Behavioral effects of alcohol are well described, however, cellular mechanisms of its action are poorly understood. There is an apparent contradiction between measurable behavioral changes produced by low concentrations of ethanol, and lack of evidence of synaptic changes at these concentrations. Furthermore, effects of ethanol on synaptic transmission in the neocortex are poorly understood. Here, we set to determine effects of ethanol on excitatory synaptic transmission in the neocortex. We show that 1-50 mm ethanol suppresses excitatory synaptic transmission to layer 2/3 pyramidal neurons in rat visual cortex in a concentration-dependent manner. To the best of our knowledge, this is the first demonstration of the effects of very low concentrations of ethanol (from 1 mm) on synaptic transmission in the neocortex. We further show that a selective antagonist of A 1 adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), blocks effects of 1-10 mm ethanol on synaptic transmission. However, the reduction in excitatory postsynaptic potential amplitude by 50 mm ethanol was not affected by DPCPX. We propose that ethanol depresses excitatory synaptic transmission in the neocortex by at least two mechanisms, engaged at different concentrations: low concentrations of ethanol reduce synaptic transmission via A 1 R-dependent mechanism and involve presynaptic changes, while higher concentrations activate additional, adenosine-independent mechanisms with predominantly postsynaptic action. Involvement of adenosine signaling in mediating effects of low concentrations of ethanol may have important implications for understanding alcohol's effects on brain function, and provide a mechanistic explanation to the interaction between alcohol and caffeine., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Endogenous extracellular adenosine level fluctuates in an activity-dependent manner and with sleep-wake cycle, modulating synaptic transmission and short-term plasticity. Hebbian-type long-term plasticity introduces intrinsic positive feedback on synaptic weight changes, making them prone to runaway dynamics. We previously demonstrated that co-occurring, weight-dependent heterosynaptic plasticity can robustly prevent runaway dynamics. Here we show that at neocortical synapses in slices from rat visual cortex, adenosine modulates the weight dependence of heterosynaptic plasticity: blockade of adenosine A 1 receptors abolished weight dependence, while increased adenosine level strengthened it. Using model simulations, we found that the strength of weight dependence determines the ability of heterosynaptic plasticity to prevent runaway dynamics of synaptic weights imposed by Hebbian-type learning. Changing the weight dependence of heterosynaptic plasticity within an experimentally observed range gradually shifted the operating point of neurons between an unbalancing regime dominated by associative plasticity and a homeostatic regime of tightly constrained synaptic changes. Because adenosine tone is a natural correlate of activity level (activity increases adenosine tone) and brain state (elevated adenosine tone increases sleep pressure), modulation of heterosynaptic plasticity by adenosine represents an endogenous mechanism that translates changes of the brain state into a shift of the regime of synaptic plasticity and learning. We speculate that adenosine modulation may provide a mechanism for fine-tuning of plasticity and learning according to brain state and activity. SIGNIFICANCE STATEMENT Associative learning depends on brain state and is impaired when the subject is sleepy or tired. However, the link between changes of brain state and modulation of synaptic plasticity and learning remains elusive. Here we show that adenosine regulates weight dependence of heterosynaptic plasticity: adenosine strengthened weight dependence of heterosynaptic plasticity; blockade of adenosine A1 receptors abolished it. In model neurons, such changes of the weight dependence of heterosynaptic plasticity shifted their operating point between regimes dominated by associative plasticity or by synaptic homeostasis. Because adenosine tone is a natural correlate of activity level and brain state, modulation of plasticity by adenosine represents an endogenous mechanism for translation of brain state changes into a shift of the regime of synaptic plasticity and learning., (Copyright © 2017 the authors 0270-6474/17/371439-14$15.00/0.)

Homosynaptic Hebbian-type plasticity provides a cellular mechanism of learning and refinement of connectivity during development in a variety of biological systems. In this review we argue that a complimentary form of plasticity-heterosynaptic plasticity-represents a necessary cellular component for homeostatic regulation of synaptic weights and neuronal activity. The required properties of a homeostatic mechanism which acutely constrains the runaway dynamics imposed by Hebbian associative plasticity have been well-articulated by theoretical and modeling studies. Such mechanism(s) should robustly support the stability of operation of neuronal networks and synaptic competition, include changes at non-active synapses, and operate on a similar time scale to Hebbian-type plasticity. The experimentally observed properties of heterosynaptic plasticity have introduced it as a strong candidate to fulfill this homeostatic role. Subsequent modeling studies which incorporate heterosynaptic plasticity into model neurons with Hebbian synapses (utilizing an STDP learning rule) have confirmed its ability to robustly provide stability and competition. In contrast, properties of homeostatic synaptic scaling, which is triggered by extreme and long lasting (hours and days) changes of neuronal activity, do not fit two crucial requirements for a hypothetical homeostatic mechanism needed to provide stability of operation in the face of on-going synaptic changes driven by Hebbian-type learning rules. Both the trigger and the time scale of homeostatic synaptic scaling are fundamentally different from those of the Hebbian-type plasticity. We conclude that heterosynaptic plasticity, which is triggered by the same episodes of strong postsynaptic activity and operates on the same time scale as Hebbian-type associative plasticity, is ideally suited to serve a homeostatic role during on-going synaptic plasticity.

Key Points: Adenosine might be the most widespread neuromodulator in the brain, but its effects on inhibitory transmission in the neocortex are not understood. Here we report that adenosine suppresses inhibitory transmission to layer 2/3 pyramidal neurons via activation of presynaptic A1 receptors. We present evidence for functional A2A receptors, which have a weak modulatory effect on the A1-mediated suppression, at about 50% of inhibitory synapses at pyramidal neurons. Adenosine suppresses excitatory and inhibitory transmission to a different extent, and can change the excitation-inhibition balance at a set of synapses bidirectionally, but on average the balance was maintained during application of adenosine. These results suggest that changes of adenosine concentration may lead to differential modulation of excitatory-inhibitory balance in pyramidal neurons, and thus redistribution of local spotlights of activity in neocortical circuits, while preserving the balanced state of the whole network., Abstract: Adenosine might be the most widespread neuromodulator in the brain: as a metabolite of ATP it is present in every neuron and glial cell. However, how adenosine affects operation of neurons and networks in the neocortex is poorly understood, mostly because modulation of inhibitory transmission by adenosine has been so little studied. To clarify adenosine's role at inhibitory synapses, and in excitation-inhibition balance in pyramidal neurons, we recorded pharmacologically isolated inhibitory responses, compound excitatory-inhibitory responses and spontaneous events in layer 2/3 pyramidal neurons in slices from rat visual cortex. We show that adenosine (1-150 μm) suppresses inhibitory transmission to these neurons in a concentration-dependent and reversible manner. The suppression was mediated by presynaptic A1 receptors (A1Rs) because it was blocked by a selective A1 antagonist, DPCPX, and associated with changes of release indices: paired-pulse ratio, inverse coefficient of variation and frequency of miniature events. At some synapses (12 out of 24) we found evidence for A2ARs: their blockade led to a small but significant increase of the magnitude of adenosine-mediated suppression. This effect of A2AR blockade was not observed when A1Rs were blocked, suggesting that A2ARs do not have their own effect on transmission, but can modulate the A1R-mediated suppression. At both excitatory and inhibitory synapses, the magnitude of A1R-mediated suppression and A2AR-A1R interaction expressed high variability, suggesting high heterogeneity of synapses in the sensitivity to adenosine. Adenosine could change the balance between excitation and inhibition at a set of inputs to a neuron bidirectionally, towards excitation or towards inhibition. On average, however, these bidirectional changes cancelled each other, and the overall balance of excitation and inhibition was maintained during application of adenosine. These results suggest that changes of adenosine concentration may lead to differential modulation of excitatory-inhibitory balance in pyramidal neurons, and thus redistribution of local spotlights of activity in neocortical circuits, while preserving the balanced state of the whole network., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Plasticity is a universal property of synapses. It is expressed in a variety of forms mediated by a multitude of mechanisms. Here we consider two broad kinds of plasticity that differ in their requirement for presynaptic activity during the induction. Homosynaptic plasticity occurs at synapses that were active during the induction. It is also called input specific or associative, and it is governed by Hebbian-type learning rules. Heterosynaptic plasticity can be induced by episodes of strong postsynaptic activity also at synapses that were not active during the induction, thus making any synapse at a cell a target to heterosynaptic changes. Both forms can be induced by typical protocols used for plasticity induction and operate on the same time scales but have differential computational properties and play different roles in learning systems. Homosynaptic plasticity mediates associative modifications of synaptic weights. Heterosynaptic plasticity counteracts runaway dynamics introduced by Hebbian-type rules and balances synaptic changes. It provides learning systems with stability and enhances synaptic competition. We conclude that homosynaptic and heterosynaptic plasticity represent complementary properties of modifiable synapses, and both are necessary for normal operation of neural systems with plastic synapses., (© The Author(s) 2014.)

Adenosine is a wide-spread endogenous neuromodulator. In the central nervous system it activates A1 and A2A receptors (A1Rs and A2ARs) which have differential distributions, different affinities to adenosine, are coupled to different G-proteins, and have opposite effects on synaptic transmission. Although effects of adenosine are studied in detail in several brain areas, such as the hippocampus and striatum, the heterogeneity of the effects of A1R and A2AR activation and their differential distribution preclude generalization over brain areas and cell types. Here we study adenosine's effects on excitatory synaptic transmission to layer 2/3 pyramidal neurons in slices of the rat visual cortex. We measured effects of bath application of adenosine receptor ligands on evoked excitatory postsynaptic potentials (EPSPs), miniature excitatory postsynaptic potentials (mEPSPs), and membrane properties. Adenosine reduced the amplitude of evoked EPSPs and excitatory postsynaptic currents (EPSCs), and reduced frequency of mEPSPs in a concentration-dependent and reversible manner. Concurrent with EPSP/C amplitude reduction was an increase in the paired-pulse ratio. These effects were blocked by application of the selective A1R antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), suggesting that activation of presynaptic A1Rs suppresses excitatory transmission by reducing release probability. Adenosine (20μM) hyperpolarized the cell membrane from -65.3±1.5 to -67.7±1.8mV, and reduced input resistance from 396.5±44.4 to 314.0±36.3MOhm (∼20%). These effects were also abolished by DPCPX, suggesting postsynaptic A1Rs. Application of the selective A2AR antagonist SCH-58261 (2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-a-mine) on the background of high adenosine concentrations revealed an additional decrease in EPSP amplitude. Moreover, application of the A2AR agonist CGS-21680 (4-[2-[[6-amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride) led to an A1R-dependent increase in mEPSP frequency. Dependence of the A2AR effects on the A1R availability suggests interaction between these receptors, whereby A2ARs exert their facilitatory effect on synaptic transmission by inhibiting the A1R-mediated suppression. Our results demonstrate functional pre and postsynaptic A1Rs and presynaptic A2ARs in layer 2/3 of the visual cortex, and suggest interaction between presynaptic A2ARs and A1Rs., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)