Distribution of Kv3.3 potassium channel subunits in distinct neuronal populations of mouse brain

Kv3.3 proteins are pore-forming subunits of voltage-dependent potassium channels, and mutations in the gene encoding for Kv3.3 have recently been linked to human disease, spinocerebellar ataxia 13, with cerebellar and extracerebellar symptoms. To understand better the functions of Kv3.3 subunits in brain, we developed highly specific antibodies to Kv3.3 and analyzed immunoreactivity throughout mouse brain. We found that Kv3.3 subunits are widely expressed, present in important forebrain structures but particularly prominent in brainstem and cerebellum. In forebrain and midbrain, Kv3.3 expression was often found colocalized with parvalbumin and other Kv3 subunits in inhibitory neurons. In brainstem, Kv3.3 was strongly expressed in auditory and other sensory nuclei. In cerebellar cortex, Kv3.3 expression was found in Purkinje and granule cells. Kv3.3 proteins were observed in axons, terminals, somas, and, unlike other Kv3 proteins, also in distal dendrites, although precise subcellular localization depended on cell type. For example, hippocampal dentate granule cells expressed Kv3.3 subunits specifically in their mossy fiber axons, whereas Purkinje cells of the cerebellar cortex strongly expressed Kv3.3 subunits in axons, somas, and proximal and distal, but not second- and third-order, dendrites. Expression in Purkinje cell dendrites was confirmed by immunoelectron microscopy. Kv3 channels have been demonstrated to rapidly repolarize action potentials and support high-frequency firing in various neuronal populations. In this study, we identified additional populations and subcellular compartments that are likely to sustain high-frequency firing because of the expression of Kv3.3 and other Kv3 subunits.     

Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin‐expressing inhibitory interneurons

The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin‐expressing (PV+) fast‐spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E–I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E–I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E–I balance in excitatory neurons.     

Long-term effects of amygdala GABA receptor blockade on specific subpopulations of hippocampal interneurons

Growing evidence indicates that the amygdala modulates hippocampal functions. To test the hypothesis that this modulation may involve long-lasting effects on interneuronal networks in the hippocampus, changes in the expression of neurochemical markers specific for different interneuronal subpopulations were assessed in adult rats 96 h following acute infusion of low doses of the GABAA receptor antagonist picrotoxin into the amygdala. The numerical density (Nd) of somata showing immunoreactivity (IR) for parvalbumin (PVB) was decreased in dentate gyrus (DG) and the CA4-2 region, while that of calretinin (CR)-IR was decreased in DG and CA2. The Nd of calbindin D28k (CB)-IR somata was decreased in CA3-2. The densities of axon terminals arising from PVB-IR and cholecystokinin (CCK)-IR basket neurons were also altered, with those of CCK-IR terminals increased across all sectors, while PVB-IR terminals were decreased only in the CA region. Increases in CCK-IR terminals were paralleled by increases of terminals with IR for the 65-kD isoform of glutamate decarboxylase (GAD65). Mixed-effects statistical models, adapted specifically for these analyses, indicated that perturbations of amygdalar inputs to the hippocampus significantly alter the drive that hippocampal PVB-, CR-, and CB-IR neurons within the dentate gyrus/CA4 region exercise on CCK-IR terminals within the same region as well as in CA3-1. These results suggest that amygdalar modulation of specific neuronal subpopulations may induce lasting and far-reaching changes in the hippocampus during normal functioning, as well as in diseases involving a disruption of amygdalar activity. In particular, changes in specific interneuronal markers within selective hippocampal sectors detected in the present results are strikingly similar to those reported in this region in schizophrenia. These similarities suggest that, in this disease, a disruption of GABAergic transmission within the amygdala may play a significant role in the induction of abnormalities in the hippocampus.     

Delayed injury of hippocampal interneurons after neonatal hypoxia‐ischemia and therapeutic hypothermia in a murine model

Delayed hippocampal injury and memory impairments follow neonatal hypoxia‐ischemia (HI) despite the use of therapeutic hypothermia (TH). Death of hippocampal pyramidal cells occurs acutely after HI, but characterization of delayed cell death and injury of interneurons (INs) is unknown. We hypothesize that injury of INs after HI is: (i) asynchronous to that of pyramidal cells, (ii) independent of injury severity, and (iii) unresponsive to TH. HI was induced in C57BL6 mice at p10 with unilateral right carotid ligation and 45 min of hypoxia (FiO₂ = 0.08). Mice were randomized to normothermia (36 °C, NT) or TH (31 °C) for 4 hr after HI and anesthesia‐exposed shams were use as controls. Brains were studied at 24 hr (p11) or 8 days (p18) after HI. Vglut1, GAD65/67, PSD95, parvalbumin (PV) and calbindin‐1 (Calb1) were measured. Cell death was assessed using cresyl violet staining and TUNEL assay. Hippocampal atrophy and astroglyosis at p18 were used to assess injury severity and to correlate with number of PV + INs. VGlut1 level decreased by 30% at 24 hr after HI, while GAD65/67 level decreased by ～50% in forebrain 8 days after HI, a decrease localized in CA1 and CA3. PSD95 levels decreased in forebrain by 65% at 24 hr after HI and remained low 8 days after HI. PV + INs increased in numbers (per mm²) and branching between p11 and p18 in sham mice but not in NT and TH mice, resulting in 21–52% fewer PV + INs in injured mice at p18. Calb1 protein and mRNA were also reduced in HI injured mice at p18. At p18, somatodendritic attrition of INs was evident in all injured mice without evidence of cell death. Neither hippocampal atrophy nor astroglyosis correlated with the number of PV + INs at p18. Thus, HI exposure has long lasting effects in the hippocampus impairing the development of the GABAergic system with only partial protection by TH independent of the degree of hippocampal injury. © 2018 Wiley Periodicals, Inc.     

Commissurally projecting inhibitory interneurons of the rat hippocampal dentate gyrus: a colocalization study of neuronal markers and the retrograde tracer Fluoro-gold.

Improved methods for detecting neuronal markers and the retrograde tracer Fluoro-Gold (FG) were used to identify commissurally projecting neurons of the rat hippocampus. In addition to the dentate hilar mossy cells and CA3 pyramidal cells shown previously to transport retrograde tracers after injection into the dorsal hippocampus, FG-positive interneurons of the dentate granule cell layer and hilus were detected in numbers greater than previously reported. FG labeling of interneurons was variable among animals, but was as high as 96% of hilar somatostatin-positive interneurons, 84% of parvalbumin-positive cells of the granule cell layer and hilus combined, and 33% of hilar calretinin-positive cells. By comparison, interneurons of the dentate molecular layer and all hippocampal subregions were conspicuously FG-negative. Whereas hilar mossy cells and CA3 pyramidal cells were FG-labeled throughout the longitudinal axis, FG-positive interneurons exhibited a relatively homotopic distribution. "Control" injections of FG into the neocortex, septum, and ventral hippocampus demonstrated that the homotopic labeling of dentate interneurons was injection site-specific, and that the CA1-CA3 interneurons unlabeled by contralateral hippocampal FG injection were nonetheless able to transport FG from the septum. These data suggest a hippocampal organizing principle according to which virtually all commissurally projecting hippocampal neurons share the property of being monosynaptic targets of dentate granule cells. Because granule cells innervate their exclusively ipsilateral target cells in a highly lamellar pattern, these results suggest that focal granule cell excitation may result in commissural inhibition of the corresponding "twin" granule cell lamella, thereby lateralizing and amplifying the influence of the initiating discharge.     

Rearrangement of synaptic connections with inhibitory neurons in developing mouse visual cortex

Cortical inhibition is determined in part by the organization of synaptic inputs to gamma-aminobutyric acidergic (GABAergic) neurons. In adult rat visual cortex, feedforward (FF) and feedback (FB) connections that link lower with higher areas provide approximately 10% of inputs to parvalbumin (PV)-expressing GABAergic neurons and approximately 90% to non-GABAergic cells (Gonchar and Burkhalter [1999] J. Comp. Neurol. 406:346-360). Although the proportions of these targets are similar in both pathways, FF synapses prefer larger PV dendrites than FB synapses, which may result in stronger inhibition in the FF than in the FB pathway (Gonchar and Burkhalter [1999] J. Comp. Neurol. 406:346-360). To determine when during postnatal (P) development FF and FB inputs to PV and non-PV neurons acquire mature proportions, and whether the pathway-specific distributions of FF and FB inputs to PV dendrites develop from a similar pattern, we studied FF and FB connections between area 17 and the higher order lateromedial area (LM) in visual cortex of P15-42 mice. We found that the innervation ratio of PV and non-PV neurons is mature at P15. Furthermore, the size distributions of PV dendrites contacted by FF and FB synapses were similar at P15 but changed during the third to sixth postnatal weeks so that, by P36-42, FF inputs preferred thick dendrites and FB synapses favored thin PV dendrites. These results suggest that distinct FF and FB circuits develop after eye opening by rearranging the distribution of excitatory synaptic inputs on the dendritic tree of PV neurons. The purpose of this transformation may be to adjust differentially the strengths of inhibition in FF and FB circuits.     

ErbB-4 and neuregulin expression in the adult mouse olfactory bulb after peripheral denervation

ErbB-4 is expressed by the periglomerular and the mitral/tufted cells of the adult mouse olfactory bulb (OB) and in the present work we tested whether this expression is regulated by the olfactory nerve input to the OB. Reversible zinc sulphate lesions of the olfactory mucosa were made in adult mice and the deafferented OB analysed by immunohistochemistry, Western blotting and semiquantitative RT-PCR. Following deafferentation, the expression of erbB-4, erbB-2 and neuregulin-1 (NRG-1) mRNAs in the OB was altered. At early stages (7-14 days) after lesion the levels of expression of olfactory marker protein (OMP), tyrosine hydroxylase (TH), erbB-4 and NRG-1 mRNAs were decreased, whilst expression of erbB-2 increased and that of NRG-2 was not significantly altered. We observed at least two distinct time courses for these expression changes. The lowest amounts of mRNA for erbB-4 and NRG-1 were observed at day 7 after lesion, whilst mRNAs for TH and OMP were lowest at day 14. At day 28 after the lesion, when olfactory receptor neuron axons had reinnervated the olfactory bulb, the expression levels of OMP, TH, erbB-2, erbB-4 and NRG-1 were identical to control values. These results indicate that the expression of erbB-4 mRNA and protein in periglomerular and mitral cells is controlled by peripheral olfactory innervation. The tight correlation in NRG-1 and erbB-4 expression levels also suggests a possible functional link that deserves further exploration.     

Preprodynorphin‐expressing neurons constitute a large subgroup of somatostatin‐expressing GABAergic interneurons in the mouse neocortex

Dynorphins, leumorphin, and neoendorphins are preprodynorphin (PPD)‐derived peptides and ligands for κ‐opioid receptors. Using an antibody to PPD C‐terminal, we investigated the chemical and molecular characteristics of PPD‐expressing neurons in mouse neocortex. PPD‐immunopositive neuronal somata were distributed most frequently in layer 5 and less frequently in layers 2–4 and 6 throughout neocortical regions. Combined labeling of immunofluorescence and fluorescent mRNA signals revealed that almost all PPD‐immunopositive neurons expressed glutamic acid decarboxylase but not vesicular glutamate transporter, indicating their γ‐aminobutyric acid (GABA)ergic characteristics, and that PPD‐immunopositive neurons accounted for 15% of GABAergic interneurons in the primary somatosensory area. As GABAergic interneurons were divided into several groups by specific markers, we further examined the chemical characteristics of PPD‐expressing neurons by the double immunofluorescence labeling method. More than 95% of PPD‐immunopositive neurons were also somatostatin (SOM)‐immunopositive in the primary somatosensory, primary motor, orbitofrontal, and primary visual areas, but only 24% were SOM‐immunopositive in the medial prefrontal cortex. In the primary somatosensory area, PPD‐immunopositive neurons constituted 50%, 79%, 55%, and 17% of SOM‐immunopositive neurons in layers 2–3, 4, 5, and 6, respectively. Although SOM‐expressing neurons contained calretinin‐, neuropeptide Y‐, nitric oxide synthase‐, and reelin‐expressing neurons as subgroups, only reelin immunoreactivity was detected in many PPD‐immunopositive neurons. These results indicate that PPD‐expressing neurons constitute a large subgroup of SOM‐expressing cortical interneurons, and the PPD/SOM‐expressing GABAergic neurons might serve not only as inhibitory elements in the local cortical circuit, but also as modulators for cortical neurons expressing κ‐opioid and/or SOM receptors. J. Comp. Neurol. 522:1506–1526, 2014. © 2013 Wiley Periodicals, Inc.     

Distinct expression of phosphorylated N-methyl-D-aspartate receptor NR1 subunits by projection neurons and interneurons in the striatum of normal and amphetamine-treated rats

N-methyl-D-aspartate (NMDA) receptors are heteromeric assemblies of subunits (NR1 and NR2A-D), and are enriched in the striatum. Receptor phosphorylation has recently been demonstrated on the NR1 subunit at three serine residues, 897, 896, and 890, which appear to correspond to the level of receptor activity. In this study, expression of phospho-specific NR1 subunits at serine 897 (pNR1S897), serine 896 (pNR1S896), or serine 890 (pNR1S890) in neurochemically identified neurons of the adult rat striatum was detected by using double-immunofluorescent labeling or combined in situ hybridization and immunohistochemistry. In both the dorsal and ventral striatum, pNR1S897 was expressed at high levels in projection neurons containing >55% dynorphin (striatonigral) and >90% enkephalin (striatopallidal) and in interneurons that were 100% positive for choline, >90% positive for parvalbumin, and >45% positive for somatostatin (co-containing neuropeptide Y and neuronal nitric oxide synthase). Low levels of pNR1S896 were present in a small portion of projection neurons (<15% for both populations of projection neurons) and were almost lacking in the three types of interneurons. Interestingly, pNR1S890 was exclusively expressed in most parvalbumin-containing interneurons (70-80%). Acute administration of a psychostimulant, amphetamine, increased the number of dynorphin-containing projection neurons and parvalbumin interneurons showing detectable levels of pNR1S896 and pNR1S890, respectively. These results demonstrate the distinct expression of phospho-NR1 subunits in different populations of striatal projection neurons and interneurons at variable levels in normal rats; they also demonstrate that phosphorylation of NR1, at least on serine 896 and 890 sites, is sensitive to drug exposure.     

"Dormant basket cell" hypothesis revisited: relative vulnerabilities of dentate gyrus mossy cells and inhibitory interneurons after hippocampal status epilepticus in the rat

The "dormant basket cell" hypothesis suggests that postinjury hippocampal network hyperexcitability results from the loss of vulnerable neurons that normally excite insult-resistant inhibitory basket cells. We have reexamined the experimental basis of this hypothesis in light of reports that excitatory hilar mossy cells are not consistently vulnerable and inhibitory basket cells are not consistently seizure resistant. Prolonged afferent stimulation that reliably evoked granule cell discharges always produced extensive hilar neuron degeneration and immediate granule cell disinhibition. Conversely, kainic acid-induced status epilepticus in chronically implanted animals produced similarly extensive hilar cell loss and immediate granule cell disinhibition, but only when granule cells discharged continuously during status epilepticus. In both preparations, electron microscopy revealed degeneration of presynaptic terminals forming asymmetrical synapses in the mossy cell target zone, including some terminating on gamma-aminobutyric acid-immunoreactive elements, but no evidence of axosomatic or axoaxonic degeneration in the adjacent granule cell layer. Although parvalbumin immunocytochemistry and in situ hybridization revealed decreased staining, this apparently was due to altered parvalbumin expression rather than basket cell death, because substance P receptor-positive interneurons, some of which contained residual parvalbumin immunoreactivity, survived. These results confirm the inherent vulnerability of dendritically projecting hilar mossy cells and interneurons and the relative resistance of dentate inhibitory basket and chandelier cells that target granule cell somata. The variability of hippocampal cell loss after status epilepticus suggests that altered hippocampal structure and function cannot be assumed to cause the spontaneous seizures that develop in these animals and highlights the importance of confirming hippocampal pathology and pathophysiology in vivo in each case.     

Developmental expression and activity variation of nitric oxide synthase in the brain of golden hamster

Nitric oxide (NO) is the downstream effector after the activation of N-methyl-D-aspartate (NMDA) receptors. It is involved in various physiological processes, such as synapse reconstruction and plasticity, neurotoxity and neuronal death. It also participates in the development and maturation of cortical neurons. The expression of nitric oxide synthase (NOS) during the postnatal development of the visual cortex was investigated by both electron spin resonance (ESR) and Western blot methods. A typical spectrum of (DETC)(2)-Fe(II)-NO complex was found in the visual cortex of different age golden hamsters by ESR method. The signal intensity increased after birth, peaked at postnatal day 14 (PD14) and then gradually decreased. An analysis of variance (ANOVA) implied that the NO synthase expression significantly correlated with the developmental processes (p < 0.05). Results of Western blot further confirmed (one-way ANOVA, p < 0.05) the developmental relating expression pattern of NO synthase shown by ESR technique.     

Developmental expression of a voltage-dependent potassium channel (Kv3.1) in auditory neurons without cochlear input.

Kv3.1, a voltage-dependent potassium channel, has two forms, -a and -b, which differ in expression during development and at the onset of function in the auditory system. To determine whether cochlear nerve input could affect the expression of these two forms, cultures of the developing cochlear nucleus were explanted in the absence of the cochlear nerve at the beginning of cell migration (Hamburger-Hamilton stage 28-30), while neuroblasts continued to migrate onto the culture substrate. After 8, 15, and 22 days in vitro (three survival groups), cultures were immunostained with antibodies recognizing either both forms of Kv3.1 or only the -b form. Only young and newly migrated nerve cells were sampled. In the three survival groups, all nerve cells expressed Kv3.1, among which only 50% or less expressed the -b form. Some of the more differentiated multipolar cells expressed the -b form, but most were labeled with the antibody that recognizes both forms. Thus, in the absence of peripheral input, both forms of Kv3.1 appear at stages very early in development, although not all cells necessarily coexpress both forms. These results agree with other observations in the chick embryo in situ. They are consistent with previous work implicating Kv3.1 in cell migration during early development.     

Localization and expression of GABA transporters in the suprachiasmatic nucleus

GABA is a principal neurotransmitter in the suprachiasmatic hypothalamic nucleus (SCN), the master circadian clock. Despite the importance of GABA and GABA uptake for functioning of the circadian pacemaker, the localization and expression of GABA transporters (GATs) in the SCN has not been investigated. The present studies used Western blot analysis, immunohistochemistry and electron microscopy to demonstrate the presence of GABA transporter 1 (GAT1) and GAT3 in the SCN. By using light microscopy, GAT1 and GAT3 were co‐localized throughout the SCN, but were not expressed in the perikarya of arginine vasopressin‐ or vasoactive intestinal peptide‐immunoreactive (‐ir) neurons of adult rats, nor in the neuronal processes labelled with the neurofilament heavy chain. Using electron microscopy, GAT1‐ and GAT3‐ir was found in glial processes surrounding unlabelled neuronal perikarya, axons, dendrites, and enveloped symmetric and asymmetric axo‐dendritic synapses. Glial fibrillary acidic protein‐ir astrocytes grown in cell culture were immunopositive for GAT1 and GAT3 and both GATs could be observed in the same glial cell. These data demonstrate that synapses in the SCN function as ‘tripartite’ synapses consisting of presynaptic axon terminals, postsynaptic membranes and astrocytes that contain GABA transporters. This model suggests that astrocytes expressing both GATs may regulate the extracellular GABA, and thereby modulate the activity of neuronal networks in the SCN.     

Developmental expression of orphan g protein-coupled receptor 50 in the mouse brain

Mental disorders have a complex etiology resulting from interactions between multiple genetic risk factors and stressful life events. Orphan G protein-coupled receptor 50 (GPR50) has been identified as a genetic risk factor for bipolar disorder and major depression in women, and there is additional genetic and functional evidence linking GPR50 to neurite outgrowth, lipid metabolism, and adaptive thermogenesis and torpor. However, in the absence of a ligand, a specific function has not been identified. Adult GPR50 expression has previously been reported in brain regions controlling the HPA axis, but its developmental expression is unknown. In this study, we performed extensive expression analysis of GPR50 and three protein interactors using rt-PCR and immunohistochemistry in the developing and adult mouse brain. Gpr50 is expressed at embryonic day 13 (E13), peaks at E18, and is predominantly expressed by neurons. Additionally we identified novel regions of Gpr50 expression, including brain stem nuclei involved in neurotransmitter signaling: the locus coeruleus, substantia nigra, and raphe nuclei, as well as nuclei involved in metabolic homeostasis. Gpr50 colocalizes with yeast-two-hybrid interactors Nogo-A, Abca2, and Cdh8 in the hypothalamus, amygdala, cortex, and selected brain stem nuclei at E18 and in the adult. With this study, we identify a link between GPR50 and neurotransmitter signaling and strengthen a likely role in stress response and energy homeostasis.     

Developmental expression of GABAA receptor subunit and GAD genes in mouse somatosensory barrel cortex

In situ hybridization histochemistry with radioactive cRNA probes was used to study patterns of gene expression for α1, α2, α4, α5, β1, β2, and γ2 subunit mRNAs of type A gamma aminobutyric acid (GABA_A) receptors and for 67-kDa glutamic acid decarboxylase (GAD₆₇) mRNA in mouse barrel cortex during the period (postnatal days 1-12; P1-P12) when thalamocortical innervation of layer IV barrels is occurring. The α1, β2, and γ2 subunit mRNAs increased substantially with age, especially in layers V and VI, and throughout the period studied, invariably had the same laminar-specific patterns of expression. All three mRNAs were highly expressed in the dense cortical plate at P1. In layer IV after differentiation of barrels, they were expressed in cells of both barrel walls and hollows but especially in the walls. The α2, α4, α5, and β1 subunit mRNAs were expressed at lower levels and had different laminar patterns of distribution; α2 and α4 showed switches between layers over time; α5 was invariably associated with the subplate or its derivative, β1 with layer IV. Levels of α2 mRNA did not change over time; α4 and β1 mRNAs increased and α5 decreased. GAD₆₇ mRNA was highest in layer I at P1 and progressively increased in other layers. These results suggest that postnatal development of GABA_A receptors is mainly directed at the production of receptors assembled from α1, β2, and γ2 subunits, with β1 contributing in layer IV. Other subunits may be associated with receptors involved in trophic actions of GABA during development and may give GABA_A receptor-mediated responses in the developing cortex their particular physiological profile. J. Comp. Neurol. 383:199-219, 1997. © 1997 Wiley-Liss, Inc.     

Western diet-induced obesity disrupts the diurnal rhythmicity of hippocampal core clock gene expression in a mouse model

Western diet (WD) feeding disrupts core clock gene expression in peripheral tissues and contributes to WD-induced metabolic disease. The hippocampus, the mammalian center for memory, is also sensitive to WD feeding, but whether the WD disrupts its core clock is unknown. To this end, male mice were maintained on a WD for 16 weeks and diurnal metabolism, gene expression and memory were assessed. WD-induced obesity disrupted the diurnal rhythms of whole-body metabolism, markers of inflammation and hepatic gene expression, but did not disrupt diurnal expression of hypothalamic Bmal1, Npas2 and Per2. However, all measured core clock genes were disrupted in the hippocampus after WD feeding and the expression pattern of genes implicated in Alzheimer’s disease and synaptic function were altered. Finally, WD feeding disrupted hippocampal memory in a task- and time-dependent fashion. Our results implicate WD-induced alterations in the rhythmicity of hippocampal gene expression in the etiology of diet-induced memory deficits.     

Neuronal and astrocyte expression of nicotinic receptor subunit beta4 in the adult mouse brain

Neuronal nicotinic acetylcholine receptor (nAChR) expression and function are customized in different brain regions through assembling receptors from closely related but genetically distinct subunits. Immunohistochemical analysis of one of these subunits, nAChRbeta4, in the mouse brain suggests an extensive and potentially diverse role for this subunit in both excitatory and inhibitory neurotransmission. Prominent immunostaining included: 1) the medial habenula, efferents composing the fasciculus retroflexus, and the interpeduncular nucleus; 2) nuclei and ascending tracts of the auditory system inclusive of the medial geniculate; 3) the sensory cortex barrel field and cell bodies of the ventral thalamic nucleus; 4) olfactory-associated structures and the piriform cortex; and 5) sensory and motor trigeminal nuclei. In the hippocampus, nAChRbeta4 staining was limited to dendrites and soma of a subset of glutamic acid dehydrogenase-positive neurons. In C57BL/6 mice, but to a lesser extent in C3H/J, CBA/J, or CF1 mice, a subpopulation of astrocytes in the hippocampal CA1 region prominently expressed nAChRbeta4 (and nAChRalpha4). Collectively, these results suggest that the unique functional and pharmacological properties exerted by nAChRbeta4 on nAChR function could modify and specialize the development of strain-specific sensory and hippocampal-related characteristics of nicotine sensitivity including the development of tolerance.