Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism

Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4–22 (Δe4–22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4–22−/− mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs

Regulation of Neuronal Excitability by Glutamate and Cholecystokinin Rodent Neocortex

174 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2005.The excitability of neuronal networks may also be modulated by neuropeptides. Cholecystokinin (CCK) is one of many neuropeptides localized in the central nervous system with relatively high concentrations in the cerebral cortex. Layer VI neocortical neurons provide important corticothalamic innervation that can modulate information processing within various thalamic nuclei. Due to the presence of CCK and its receptors in deep layer neocortex, I have examined the actions of CCK on the excitability of deep layer neocortical neurons. CCK produced a robust depolarization in layer VI pyramidal neurons that was associated with an increase in apparent input resistance and persisted in tetrodotoxin. This depolarization was mediated by CCKB subtype receptors, and resulted from a reduced linear K+ current as well as an increase in a nonselective cation current. I also found that CCK produces excitatory responses in layer V pyramidal and nonpyramidal neurons. Given the potentially important role of corticothalamic innervation, the long-lasting excitation of deep neocortical neurons by CCK could modulate their output and ultimately have an important influence on information transfer through the thalamocortical circuit.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Regulation of Neuronal Excitability by Glutamate and Cholecystokinin Rodent Neocortex

174 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2005.The excitability of neuronal networks may also be modulated by neuropeptides. Cholecystokinin (CCK) is one of many neuropeptides localized in the central nervous system with relatively high concentrations in the cerebral cortex. Layer VI neocortical neurons provide important corticothalamic innervation that can modulate information processing within various thalamic nuclei. Due to the presence of CCK and its receptors in deep layer neocortex, I have examined the actions of CCK on the excitability of deep layer neocortical neurons. CCK produced a robust depolarization in layer VI pyramidal neurons that was associated with an increase in apparent input resistance and persisted in tetrodotoxin. This depolarization was mediated by CCKB subtype receptors, and resulted from a reduced linear K+ current as well as an increase in a nonselective cation current. I also found that CCK produces excitatory responses in layer V pyramidal and nonpyramidal neurons. Given the potentially important role of corticothalamic innervation, the long-lasting excitation of deep neocortical neurons by CCK could modulate their output and ultimately have an important influence on information transfer through the thalamocortical circuit.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Therapeutic approaches for shankopathies

Despite recent advances in understanding the molecular mechanisms of autism spectrum disorders (ASD), the current treatments for these disorders are mostly focused on behavioral and educational approaches. The considerable clinical and molecular heterogeneity of ASD present a significant challenge to the development of an effective treatment targeting underlying molecular defects. Deficiency of SHANK family genes causing ASD represent an exciting opportunity for developing molecular therapies because of strong genetic evidence for SHANK as causative genes in ASD and the availability of a panel of Shank mutant mouse models. In this article, we review the literature suggesting the potential for developing therapies based on molecular characteristics and discuss several exciting themes that are emerging from studying Shank mutant mice at the molecular level and in terms of synaptic function

The whisking oscillator circuit

Central oscillators are primordial neural circuits that generate and control rhythmic movements1,2. Mechanistic understanding of these circuits requires genetic identification of the oscillator neurons and their synaptic connections to enable targeted electrophysiological recording and causal manipulation during behaviours. However, such targeting remains a challenge with mammalian systems. Here we delimit the oscillator circuit that drives rhythmic whisking-a motor action that is central to foraging and active sensing in rodents3,4. We found that the whisking oscillator consists of parvalbumin-expressing inhibitory neurons located in the vibrissa intermediate reticular nucleus (vIRtPV) in the brainstem. vIRtPV neurons receive descending excitatory inputs and form recurrent inhibitory connections among themselves. Silencing vIRtPV neurons eliminated rhythmic whisking and resulted in sustained vibrissae protraction. In vivo recording of opto-tagged vIRtPV neurons in awake mice showed that these cells spike tonically when animals are at rest, and transition to rhythmic bursting at the onset of whisking, suggesting that rhythm generation is probably the result of network dynamics, as opposed to intrinsic cellular properties. Notably, ablating inhibitory synaptic inputs to vIRtPV neurons quenched their rhythmic bursting, impaired the tonic-to-bursting transition and abolished regular whisking. Thus, the whisking oscillator is an all-inhibitory network and recurrent synaptic inhibition has a key role in its rhythmogenesis

Midbrain Dopamine Controls Anxiety-like Behavior by Engaging Unique Interpeduncular Nucleus Microcircuitry

BACKGROUND: Dopamine (DA) is hypothesized to modulate anxiety-like behavior, although the precise role of DA in anxiety behaviors and the complete anxiety network in the brain have yet to be elucidated. Recent data indicate that dopaminergic projections from the ventral tegmental area (VTA) innervate the interpeduncular nucleus (IPN), but how the IPN responds to DA and what role this circuit plays in anxiety-like behavior are unknown. METHODS: We expressed a genetically encoded G protein-coupled receptor activation-based DA sensor in mouse midbrain to detect DA in IPN slices using fluorescence imaging combined with pharmacology. Next, we selectively inhibited or activated VTA--\u3eIPN DAergic inputs via optogenetics during anxiety-like behavior. We used a biophysical approach to characterize DA effects on neural IPN circuits. Site-directed pharmacology was used to test if DA receptors in the IPN can regulate anxiety-like behavior. RESULTS: DA was detected in mouse IPN slices. Silencing/activating VTA--\u3eIPN DAergic inputs oppositely modulated anxiety-like behavior. Two neuronal populations in the ventral IPN (vIPN) responded to DA via D1 receptors (D1Rs). vIPN neurons were controlled by a small population of D1R neurons in the caudal IPN that directly respond to VTA DAergic terminal stimulation and innervate the vIPN. IPN infusion of a D1R agonist and antagonist bidirectionally controlled anxiety-like behavior. CONCLUSIONS: VTA DA engages D1R-expressing neurons in the caudal IPN that innervate vIPN, thereby amplifying the VTA DA signal to modulate anxiety-like behavior. These data identify a DAergic circuit that mediates anxiety-like behavior through unique IPN microcircuitry