Development of whisker-specific neural patterns in the rodent somatosensory system requires NMDA receptor (NMDAR)-mediated activity. In cortex-specific NR1 knockout (CxNR1KO) mice, while thalamocortical afferents (TCAs) develop rudimentary whisker-specific patterns in the primary somatosensory (barrel) cortex, layer IV cells do not develop barrels or orient their dendrites towards TCAs. To determine the role of postsynaptic NMDARs in presynaptic afferent development and patterning in the barrel cortex, we examined the single TCA arbors in CxNR1KO mice between postnatal days (P) 1-7. Sparsely branched TCAs invade the cortical plate on P1 in CxNR1KO mice as in control mice. In control animals, TCAs progressively elaborate patchy terminals, mostly restricted to layer IV. In CxNR1KO mice, TCAs develop far more extensive arbors between P3-7. Their lateral extent is twice that of controls from P3 onwards. By P7, CxNR1KO TCAs have significantly fewer branch points and terminal endings in layers IV and VI but more in layers II/III and V than control mouse TCAs. Within expansive terminal arbors, CxNR1KO TCAs develop focal terminal densities in layer IV, corresponding to the rudimentary whisker-specific patches. Given that thalamic NMDARs are spared in CxNR1KO mice, the present results show that postsynaptic NMDARs play an important role in refinement of presynaptic afferent arbors and whisker-specific patterning in the developing barrel cortex. Indexing termsbarrels; barreloids; trigeminal system; somatosensory cortex; region-specific gene knockout A conspicuous feature of the rodent primary somatosensory cortex is the presence of neural patterns within face and digit representation regions of the body map. Patches of thalamocortical afferent (TCA) arbors and their postsynaptic partners form discrete modules that replicate the patterned distribution of whiskers on the contralateral snout. These cellular modules are termed "barrels" (Woolsey and Van der Loos, 1970). Whisker and digit-related patterns are first established in the brainstem somatosensory nuclei, then in the ventrobasal nuclear complex (VB) of the dorsal thalamus, and finally in the layer IV of the neocortex. Such cellular modules are called "barreloids" in the VB, and "barrelettes" in the brainstem (Woolsey and Van der Loos, 1970;Van der Loos, 1976;Ma and Woolsey, 1984 Van der Loos, 1986;Woolsey, 1990;O'Leary et al., 1994;Killackey et al., 1995). Several lines of evidence also indicate that somatosensory periphery-related neural maps and patterns are conveyed to target cells by the afferents at each synaptic relay station Jhaveri, 1990, 1992a, b;Senft and Woolsey, 1991).In recent years, a number of transgenic and knockout (KO) mouse models have begun yielding clues to the underlying mechanisms of pattern formation in the rodent somatosensory system, with profound implications for other sensory pathways in the mammalian brain. Current understanding is that topographically organized projections (somatotopic maps) along the somatosensory system are es...

Selective serotonin reuptake inhibitor (SSRI)-type antidepressants are often prescribed to depressive pregnant women for their less adverse side effects. However, growing evidences have shown increased congenital malformations and poor neonatal adaptation in the perinatal SSRI-exposed human infants as well as animal pups. In this study, we examined the effects of early exposure of fluoxetine, the most popular SSRI-type antidepressant, on the developing somatosensory system. Physiological saline or fluoxetine (10 mg/kg) was subcutaneously injected into neonatal rats from P0 to P6. Somatosensory-related behaviors were examined in adolescence (P30-P35). Morphological features of the primary somatosensory cortex were checked at P7 and P35. The tactile and thermal perceptions as well as locomotor activity were affected by neonatal fluoxetine treatment. At the morphological level, the number of branch tips of thalamocortical afferents to the somatosensory cortex was reduced in the fluoxetine-treated rats. Furthermore, the spiny stellate neurons in the layer IV somatosensory cortex had reduced dendritic span and complexity with fewer branches, shorter dendritic length, and smaller dendritic field. The spine density of spiny stellate neurons was significantly reduced whereas the spine length of mushroom- and branched-type was increased. Taken together, these results indicate that neonatal fluoxetine administration has long-lasting effects on the function and structure in the somatosensory system. Sensory information processing may be disturbed in the neonatal fluoxetine-treated animals due to the structural deformation in the thalamocortical afferents and dendritic structures of the spiny stellate neurons in the layer IV somatosensory cortex.

In the rodent trigeminal principal nucleus (PrV), trigeminal afferent terminals and postsynaptic cells form discrete modules ("barrelettes") that replicate the patterned array of whiskers and sinus hairs on the snout. Barrelette neurons of the PrV relay whisker-specific patterns to the contralateral thalamus and, subsequently, to the primary somatosensory barrel cortex. Genetic impairment of NMDA receptor (NMDAR) function blocks development of barrelettes in the PrV. Underlying cellular and functional defects are not known. Here, we examined morphological differentiation of whisker afferents, dendritic differentiation of barrelette cells, and their electrophysiological properties in mice with genetic perturbations of the essential subunit NR1 of NMDARs. We show that in NR1 gene knock-down (KD) and knock-out mice, whisker afferents begin their embryonic development normally but, over time, fail to segregate into patches, and instead they develop exuberant terminal arbors spanning most of the PrV. Postnatal NR1KD barrelette cells, with significantly reduced NMDA currents, retain their membrane and synaptic properties but develop longer dendrites with no orientation preference. These results indicate that NMDARs regulate growth of presynaptic terminal arbors and postsynaptic dendritic branching, thereby leading to consolidation of synapses and patterning of presynaptic and postsynaptic elements.

The mesocorticolimbic system contains dopamine (DA)-producing neurons in the ventral tegmental area (VTA) and their projection targets, including the medial prefrontal cortex (mPFC), amygdala (AMY) and nucleus accumbens (NAc). Disruption of this system might attribute to mental illnesses. In the present study, we adopted the postweaning social isolation paradigm to model neuropsychiatric disorders and studied the functional and structural changes of the mesocorticolimbic system. After 8-9 weeks of isolation, rats exhibited hyperlocomotor activity and impaired sensorimotor gating compared to group-reared controls. However, the number of tyrosine hydroxylase-positive VTA neurons and the volume of VTA were not affected. Comparing with group-reared controls, the DA levels in the isolation-reared were not altered in the VTA, mPFC and NAc but decreased in the AMY. In the structural aspect, dendritic features of layer II/III pyramidal mPFC neurons; pyramidal neurons in the basolateral nucleus of amygdala (BLA) and medium spiny neurons in the core region of the NAc (NAcc) were examined. Interestingly, the neuronal changes were region-specific. The mPFC neurons had reduced dendritic complexity, spine density and elongated terminal branches. The BLA neurons had extensive dendritic arbors with short branches but unchanged spine density. The NAcc neurons had reduced total dendritic length but the segment length and spine density remained the same. Together, the results demonstrated the structural and functional changes in the mesocorticolimbic DA system of socially isolated rats. These changes may account for the behavioral impairments in these rats and attribute to the susceptibility to mental disorders related to schizophrenia and depression.

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RBFOX3 mutations are linked to epilepsy and cognitive impairments, but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3. Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway. The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders.

Serotonin (5-HT) plays important roles during neural development. Administration of selective serotonin reuptake inhibitor (SSRI)-type medication during gestation may influence the maturation of the fetal brain and subsequent brain functions. To mimic the condition of late-gestation SSRI exposure, we administered fluoxetine (FLX) in neonatal rats during the first postnatal week, which roughly corresponds to the third trimester period of human gestation. FLX-exposed adult male rats exhibited reduced locomotor activity and depression-like behaviors. Furthermore, sensorimotor gating capacity was also impaired. Interestingly, increased social interaction was noticed in FLX-exposed rats. When the levels of 5-HT and tryptophan hydroxylase were examined, no significant changes were found in FLX rats compared to control (CON) rats. The behavioral phenotypes of FLX rats suggested malfunction of the limbic system. Dendritic architectures of neurons in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) were examined. Layer II/III mPFC pyramidal neurons in FLX rats had exuberant dendritic branches with elongated terminal segments compared to those in CON rats. In BLA pyramidal neurons, the dendritic profiles were comparable between the two groups. However, in FLX rats, the density of dendritic spines was reduced in both mPFC and BLA. Together, our results demonstrated the long-lasting effects of early FLX treatment on emotional and social behaviors in adult rats in which impaired neuronal structure in the limbic system was also noticed. The risk of taking SSRI-type antidepressants during pregnancy should be considered.

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