A Versatile Synthetic Affinity Probe Reveals Inhibitory Synapse Ultrastructure and Brain Connectivity.

Visualization of inhibitory synapses requires protocol tailoring for different sample types and imaging techniques, and usually relies on genetic manipulation or the use of antibodies that underperform in tissue immunofluorescence. Starting from an endogenous ligand of gephyrin, a universal marker of the inhibitory synapse, we developed a short peptidic binder and dimerized it, significantly increasing affinity and selectivity. We further tailored fluorophores to the binder, yielding "Sylite"-a probe with outstanding signal-to-background ratio that outperforms antibodies in tissue staining with rapid and efficient penetration, mitigation of staining artifacts, and simplified handling. In super-resolution microscopy Sylite precisely localizes the inhibitory synapse and enables nanoscale measurements. Sylite profiles inhibitory inputs and synapse sizes of excitatory and inhibitory neurons in the midbrain and combined with complimentary tracing techniques reveals the synaptic connectivity.

Adenosine A1 and A2A receptors differently control synaptic plasticity in the mouse dorsal and ventral hippocampus.

The hippocampus is a brain region involved in processing both memory and emotions, through a preferential involvement of the dorsal hippocampus (DH) and ventral hippocampus (VH), respectively. Adenosine A1 and A2A receptors (A1 R and A2A R) control both mood and memory, but it is not known if there is a different adenosine modulation of synaptic plasticity along the hippocampal axis. Using adult, C57BL/6 male mice, we show that both A1 R and A2A R were more abundant in DH compared with VH. However, recordings of field excitatory postsynaptic potentials at Schaffer collaterals-CA1 pyramidal synapses revealed that A1 R were equi-effective to inhibit basal excitatory synaptic transmission in DH and VH, but endogenous A1 R activation was more effective to depress the probability of release in VH. In contrast, the selective A2A R antagonist (SCH58261, 50 nM) controlled both long-term potentiation (induced by a high frequency stimulation protocol) and long-term depression (induced by a low frequency stimulation protocol) selectively in DH rather than VH, whereas the selective A1 R antagonist (DPCPX, 100 nM) revealed a similar tonic inhibition of long-term depression in DH and VH. These findings show a different control of synaptic plasticity by the adenosine modulation system in the dorsal and ventral poles of the hippocampus, which may underlie a different efficiency of the adenosine system to control mood and memory.

From synaptic dysfunction to atypical emotional processing in autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition mainly characterized by social impairments and repetitive behaviors. Among these core symptoms, a notable aspect of ASD is the presence of emotional complexities, including high rates of anxiety disorders. The inherent heterogeneity of ASD poses a unique challenge in understanding its etiological origins, yet the utilization of diverse animal models replicating ASD traits has enabled researchers to dissect the intricate relationship between autism and atypical emotional processing. In this review, we delve into the general findings about the neural circuits underpinning one of the most extensively researched and evolutionarily conserved emotional states: fear and anxiety. Additionally, we explore how distinct ASD animal models exhibit various anxiety phenotypes, making them a crucial tool for dissecting ASD's multifaceted nature. Overall, to a proper display of fear response, it is crucial to properly process and integrate sensorial and visceral cues to the fear-induced stimuli. ASD individuals exhibit altered sensory processing, possibly contributing to the emergence of atypical phobias, a prevailing anxiety disorder manifested in this population. Moreover, these individuals display distinctive alterations in a pivotal fear and anxiety processing hub, the amygdala. By examining the neurobiological mechanisms underlying fear and anxiety regulation, we can gain insights into the factors contributing to the distinctive emotional profile observed in individuals with ASD. Such insights hold the potential to pave the way for more targeted interventions and therapies that address the emotional challenges faced by individuals within the autism spectrum.