Somatodendritic (STD) dopamine (DA) release is a key mechanism for the autoregulatory control of DA release in the brain. However, its molecular mechanism remains undetermined. We tested the hypothesis that differential expression of synaptotagmin (Syt) isoforms explains some of the differential properties of terminal and STD DA release. Down-regulation of the dendritically expressed Syt4 and Syt7 severely reduced STD DA release, whereas terminal release required Syt1. Moreover, we found that although mobilization of intracellular Ca 2؉ stores is inefficient, Ca 2؉ influx through N-and P/Q-type voltage-gated channels is critical to trigger STD DA release. Our findings provide an explanation for the differential Ca 2؉ requirement of terminal and STD DA release. In addition, we propose that not all sources of intracellular Ca 2؉ are equally efficient to trigger this release mechanism. Our findings have implications for a better understanding of a fundamental cell biological process mediating transcellular signaling in a system critical for diseases such as Parkinson disease. Dopamine (DA),4 like other monoamine neurotransmitters, is released from the cell body and dendrites in addition to axon terminals (1). This process, called somatodendritic (STD) release, is important in the ventral tegmental area (VTA) for induction of behavioral sensitization to amphetamine through activation of local D1 receptors (2, 3) and in the substantia nigra (SN) for control of motor performance (4, 5). In addition, STD DA release modulates DA neuron firing activity through D2 autoreceptor activation (6, 7) and increases firing activity of SN pars reticulata ␥-aminobutyric acid-releasing neurons, a process that might activate feedback signals regulating DA neuron activity (8), thereby influencing axonal DA release.Two mechanisms have been proposed to mediate STD DA release: reversal of the DA transporter (9) and a vesicular exocytotic-like mechanism. In agreement with the second mechanism, STD DA release is activity-dependent (6, 10), sensitive to depletion of vesicular stores with reserpine (6, 11, 12), and Ca 2ϩ -dependent (6, 10, 12, 13). Moreover, disruption of SNARE proteins with botulinum toxins blocks STD DA release (10, 13). Vesicular exocytosis requires the concerted action of SNARE proteins and a synaptotagmin (Syt). During release, SNAREs have a direct role in vesicle-membrane fusion, and Syt acts as a Ca 2ϩ sensor. Of the 15 Syt isoforms identified so far, Syt1, 2, 3, 5, 6, 7, 9, and 10 have been reported to drive Ca 2ϩ -dependent vesicular fusion (14), and only Syt1, 2, and 9 are confirmed as Ca 2ϩ sensors for synaptic neurotransmitter release from axon terminals (15).One of the hallmarks of STD DA release is its relative persistence at reduced levels of extracellular Ca 2ϩ concentrations: although release from axon terminals is drastically reduced at extracellular Ca 2ϩ levels lower than 1 mM, STD DA release persists at Ca 2ϩ levels between 0.5 and 1 mM (Refs. 10, 12, and 13; but see also Ref. 16). This differential Ca 2...

Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans.

Neocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. Here, we show that ChAT-VIP neurons directly excite neighbouring neurons in several layers through fast synaptic transmission of acetylcholine (ACh) in rodent medial prefrontal cortex (mPFC). Both interneurons in layers (L)1–3 as well as pyramidal neurons in L2/3 and L6 receive direct inputs from ChAT-VIP neurons mediated by fast cholinergic transmission. A fraction (10–20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons. Finally, we show that activity of these neurons is relevant for behaviour and they control attention behaviour distinctly from basal forebrain ACh inputs. Thus, ChAT-VIP neurons are a local source of cortical ACh that directly excite neurons throughout cortical layers and contribute to attention.

Activity flow through the hippocampus is thought to arise exclusively from unidirectional excitatory synaptic signaling from CA3 to CA1 to the subiculum. Theta rhythms are important for hippocampal synchronization during episodic memory processing; thus, it is assumed that theta rhythms follow these excitatory feedforward circuits. To the contrary, we found that theta rhythms generated in the rat subiculum flowed backward to actively modulate spike timing and local network rhythms in CA1 and CA3. This reversed signaling involved GABAergic mechanisms. However, when hippocampal circuits were physically limited to a lamellar slab, CA3 outputs synchronized CA1 and the subiculum using excitatory mechanisms, as predicted by classic hippocampal models. Finally, analysis of in vivo recordings revealed that this reversed theta flow was most prominent during REM sleep. These data demonstrate that communication between CA3, CA1 and the subiculum is not exclusively unidirectional or excitatory and that reversed inhibitory theta signaling also contributes to intrahippocampal synchrony.