Neonatal vocalization is structurally altered in mouse models of autism spectrum disorder (ASD). Our published data showed that pup vocalization, under conditions of maternal separation, contains sequences whose alterations in a genetic mouse model of ASD impair social communication between pups and mothers. We describe details of a method which reveals the statistical structure of call sequences that are functionally critical for optimal maternal care. Entropy analysis determines the degree of non-random call sequencing. A Markov model determines the actual call sequences used by pups. Sparse partial least squares discriminant analysis (sPLS-DA) identifies call sequences that differentiate groups and reveals the degrees of individual variability in call sequences between groups. These three sets of analyses can be used to identify the otherwise hidden call structure that is altered in mouse models of developmental neuropsychiatric disorders, including not only autism but also schizophrenia. © 2018 by John Wiley & Sons, Inc.
Thalamocortical network dysfunction contributes to seizures and sleep deficits in Dravet syndrome (DS), an infantile epileptic encephalopathy, but the underlying molecular and cellular mechanisms remain elusive. DS is primarily caused by mutations in the SCN1A gene encoding the voltage-gated sodium channel Nav1.1, which is highly expressed in GABAergic reticular thalamus (nRT) neurons as well as glutamatergic thalamocortical neurons. We hypothesized that Nav1.1 haploinsufficiency alters somatosensory corticothalamic circuit function through both intrinsic and synaptic mechanisms in nRT and thalamocortical neurons. Using Scn1a heterozygous mice of both sexes aged P25-P30, we discovered reduced intrinsic excitability in nRT neurons and thalamocortical neurons in the ventral posterolateral (VPL) thalamus, while thalamocortical ventral posteromedial (VPM) neurons exhibited enhanced excitability. Nav1.1 haploinsufficiency enhanced GABAergic synaptic input and reduced ascending glutamatergic sensory input to VPL neurons, but not VPM neurons. In addition, glutamatergic cortical input to nRT neurons was reduced in Scn1a heterozygous mice, whereas cortical input to VPL and VPM neurons remained unchanged. These findings introduce input-specific alterations in glutamatergic synapse function and aberrant glutamatergic neuron excitability in the thalamus as disease mechanisms in Dravet syndrome, which has been widely considered a disease of GABAergic neurons. This work reveals additional complexity that expands current models of thalamic dysfunction in Dravet syndrome and identifies new components of corticothalamic circuitry as potential therapeutic targets.
Somatosensory information is propagated from the periphery to the cerebral cortex by two parallel pathways through the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus. VPL and VPM neurons receive somatosensory signals from the body and head, respectively. VPL and VPM neurons also receive cell-type-specific GABAergic input from the reticular nucleus of the thalamus (nRT). Although VPL and VPM neurons have distinct connectivity and physiological roles, differences in the functional properties of VPL and VPM neurons remain unclear as they are often studied as one ventrobasal (VB) thalamus neuron population. Here, we directly compared synaptic and intrinsic properties of VPL and VPM neurons in C57Bl/6J mice of both sexes aged P25-P32. Recordings of spontaneous synaptic transmission suggested that VPL neurons receive excitatory synaptic input with higher frequency and strength than VPM neurons, while VPL neurons exhibited weaker inhibitory synapse strength than VPM neurons. Furthermore, VPL neurons showed enhanced depolarization-induced spike firing and greater spike frequency adaptation than VPM neurons. VPL and VPM neurons fired similar numbers of spikes during hyperpolarization rebound bursts, but VPM neurons exhibited shorter burst latency compared to VPL neurons, which correlated with increased sag potential during hyperpolarization. This work indicates that VPL and VPM thalamocortical neurons are functionally distinct populations. The observed functional differences could have important implications for their specific physiological and pathophysiological roles within the somatosensory thalamocortical network.
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