ABSTRACT
In Alzheimer's disease (AD), network hyperexcitability is frequently observed and associated with subsequent cognitive impairment. Dysfunction of inhibitory interneurons (INs) is thought to be one of the key biological mechanisms of hyperexcitability. However, it is still unknown how INs are functionally affected in tau pathology, which is a major pathology in AD. To clarify this, we evaluated the neuronal activity of cortical INs in 6-month-old rTg4510 mice, a model of tauopathy. Calcium imaging with mDlx enhancer-driven labeling revealed that neuronal activity in INs was decreased in rTg4510 mice. In the patch clamp recording, the firing properties of fast-spiking INs were altered so as to reduce their activity in rTg4510 mice. In parallel with microglial activation, perineuronal nets around parvalbumin-positive INs were partially disrupted in rTg4510 mice. Taken together, our data indicate that the excitability of cortical fast-spiking INs is decreased, possibly because of the disruption of perineuronal nets.
ABSTRACT
Activation of mu-opioid receptor (MOR) disinhibits dopaminergic neurons in the ventral tegmental area (VTA) through inhibition of γ-aminobutyric acid (GABA)ergic neurons. This mechanism is thought to play a pivotal role in mediating reward behaviors. Here, we characterised VTA-projecting enkephalinergic neurons in the anterior division of the bed nucleus of the stria terminalis (BST) and investigated their targets by examining MOR expression in the VTA. In the BST, neurons expressing preproenkephalin mRNA were exclusively GABAergic, and constituted 37.2% of the total GABAergic neurons. Using retrograde tracer injected into the VTA, 21.6% of VTA-projecting BST neurons were shown to express preproenkephalin mRNA. Enkephalinergic projections from the BST exclusively formed symmetrical synapses onto the dendrites of VTA neurons. In the VTA, 74.1% of MOR mRNA-expressing neurons were GABAergic, with the rest being glutamatergic neurons expressing type-2 vesicular glutamate transporter mRNA. However, MOR mRNA was below the detection threshold in dopaminergic neurons. By immunohistochemistry, MOR was highly expressed on the extrasynaptic membranes of dendrites in GABAergic VTA neurons, including dendrites innervated by BST-VTA projection terminals. MOR was also expressed weakly on GABAergic and glutamatergic terminals in the VTA. Given that GABAA α1 is expressed at GABAergic BST-VTA synapses on dendrites of GABAergic neurons [T. Kudo et al. (2012) J. Neurosci., 32, 18035-18046], our results collectively indicate that the BST sends dual inhibitory outputs targeting GABAergic VTA neurons; GABAergic inhibition via 'wired' transmission, and enkephalinergic inhibition via 'volume' transmission. This dual inhibitory system provides the neural substrate underlying the potent disinhibitory control over dopaminergic VTA neurons exerted by the BST.
Subject(s)
Enkephalins/metabolism , GABAergic Neurons/metabolism , Protein Precursors/metabolism , Septal Nuclei/metabolism , Ventral Tegmental Area/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Axons/metabolism , Cells, Cultured , Dendrites/metabolism , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/physiology , Enkephalins/genetics , GABAergic Neurons/physiology , Mice , Mice, Inbred C57BL , Neural Inhibition , Neuropil/metabolism , Protein Precursors/genetics , Protein Transport , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, GABA-A/genetics , Receptors, GABA-A/metabolism , Receptors, Opioid, mu/genetics , Receptors, Opioid, mu/metabolism , Septal Nuclei/cytology , Septal Nuclei/physiology , Ventral Tegmental Area/cytology , Ventral Tegmental Area/physiology , Vesicular Glutamate Transport Protein 2/genetics , Vesicular Glutamate Transport Protein 2/metabolismABSTRACT
Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) play crucial roles in motivational control of behaviors, and their activity is regulated directly or indirectly via GABAergic neurons by extrinsic afferents from various sources, including the bed nucleus of the stria terminalis (BST). Here, the neurochemical composition of VTA-projecting BST neurons and their outputs to the VTA were studied in adult mouse brains. By combining retrograde tracing with fluorescence in situ hybridization for 67 kDa glutamate decarboxylase (GAD67) and vesicular glutamate transporters (VGluTs), VTA-targeting BST neurons were classified into GAD67-positive (GAD67(+))/VGluT3-negative (VGluT3(-)), GAD67(+)/VGluT3(+), and VGluT2(+) neurons, of which GAD67(+)/VGluT3(-) neurons constituted the majority (â¼90%) of VTA-projecting BST neurons. GABAergic efferents from the BST formed symmetrical synapses on VTA neurons, which were mostly GABAergic neurons, and expressed GABA(A) receptor α1 subunit on their synaptic and extrasynaptic membranes. In the VTA, VGluT3 was detected in terminals expressing vesicular inhibitory amino acid transporter (VIAAT), plasmalemmal serotonin transporter, or neither. Of these, VIAAT(+)/VGluT3(+) terminals, which should include those from GAD67(+)/VGluT3(+) BST neurons, formed symmetrical synapses. When single axons from VGluT3(+) BST neurons were examined, almost all terminals were labeled for VIAAT, whereas VGluT3 was often absent from terminals with high VIAAT loads. VGluT2(+) terminals in the VTA exclusively formed asymmetrical synapses, which expressed AMPA receptors on postsynaptic membrane. Therefore, the major mode of the BST-VTA projection is GABAergic, and its activation is predicted to disinhibit VTA DAergic neurons. VGluT2(+) and VGluT3(+) BST neurons further supply additional projections, which may principally convey excitatory or inhibitory inputs, respectively, to the VTA.
