ABSTRACT
In the rodent whisker system, active sensing and sensorimotor integration are mediated in part by the dynamic interactions between the motor cortex (M1) and somatosensory cortex (S1). However, understanding these dynamic interactions requires knowledge about the synapses and how specific neurons respond to their input. Here, we combined optogenetics, retrograde labeling, and electrophysiology to characterize the synaptic connections between M1 and layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons in S1 of mice (both sexes). We found that M1 synapses onto IT cells displayed modest short-term depression, whereas synapses onto PT neurons showed robust short-term facilitation. Despite M1 inputs to IT cells depressing, their slower kinetics resulted in summation and a response that increased during short trains. In contrast, summation was minimal in PT neurons due to the fast time course of their M1 responses. The functional consequences of this reduced summation, however, were outweighed by the strong facilitation at these M1 synapses, resulting in larger response amplitudes in PT neurons than IT cells during repetitive stimulation. To understand the impact of facilitating M1 inputs on PT output, we paired trains of inputs with single backpropagating action potentials, finding that repetitive M1 activation increased the probability of bursts in PT cells without impacting the time dependence of this coupling. Thus, there are two parallel but dynamically distinct systems of M1 synaptic excitation in L5 of S1, each defined by the short-term dynamics of its synapses, the class of postsynaptic neurons, and how the neurons respond to those inputs.
Subject(s)
Motor Cortex , Optogenetics , Somatosensory Cortex , Animals , Somatosensory Cortex/physiology , Motor Cortex/physiology , Male , Female , Neural Pathways/physiology , Synapses/physiology , Mice , Neurons/physiology , Mice, Inbred C57BL , Vibrissae/physiology , Pyramidal Tracts/physiology , Mice, Transgenic , Excitatory Postsynaptic Potentials/physiologyABSTRACT
Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments, neurobehavioral phenotypes including autism and attention deficit hyperactivity disorder (ADHD), and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts to GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss of function that will pave the way for future molecular studies into DESSH. These studies begin to uncover some biological underpinnings of DESSH syndrome and elucidate the biology of Wac, with advantages in each model.
ABSTRACT
In the rodent whisker system, active sensing and sensorimotor integration are mediated in part by the dynamic interactions between the motor cortex (M1) and somatosensory cortex (S1). However, understanding these dynamic interactions requires knowledge about the synapses and how specific neurons respond to their input. Here, we combined optogenetics, retrograde labeling, and electrophysiology to characterize the synaptic connections between M1 and layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons in S1 of mice (both sexes). We found that M1 synapses onto IT cells displayed modest short-term depression, whereas synapses onto PT neurons showed robust short-term facilitation. Despite M1 inputs to IT cells depressing, their slower kinetics resulted in summation and a response that increased during short trains. In contrast, summation was minimal in PT neurons due to the fast time course of their M1 responses. The functional consequences of this reduced summation, however, were outweighed by the strong facilitation at these M1 synapses, resulting in larger response amplitudes in PT neurons than IT cells during repetitive stimulation. To understand the impact of facilitating M1 inputs on PT output, we paired trains of inputs with single backpropagating action potentials, finding that repetitive M1 activation increased the probability of bursts in PT cells without impacting the time-dependence of this coupling. Thus, there are two parallel but dynamically distinct systems of M1 synaptic excitation in L5 of S1, each defined by the short-term dynamics of its synapses, the class of postsynaptic neurons, and how the neurons respond to those inputs.
ABSTRACT
Short-term plasticity regulates the strength of central synapses as a function of previous activity. In the neocortex, direct synaptic interactions between areas play a central role in cognitive function, but the activity-dependent regulation of these long-range corticocortical connections and their impact on a postsynaptic target neuron is unclear. Here, we use an optogenetic strategy to study the connections between mouse primary somatosensory and motor cortex. We found that short-term facilitation was strong in both corticocortical synapses, resulting in far more sustained responses than local intracortical and thalamocortical connections. A major difference between pathways was that the synaptic strength and magnitude of facilitation were distinct for individual excitatory cells located across all cortical layers and specific subtypes of GABAergic neurons. Facilitation was dependent on the presynaptic calcium sensor synaptotagmin-7 and altered by several optogenetic approaches. Current-clamp recordings revealed that during repetitive activation, the short-term dynamics of corticocortical synapses enhanced the excitability of layer 2/3 pyramidal neurons, increasing the probability of spiking with activity. Furthermore, the properties of the connections linking primary with secondary somatosensory cortex resemble those between somatosensory-motor areas. These short-term changes in transmission properties suggest long-range corticocortical synapses are specialized for conveying information over relatively extended periods.