Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain

In mammals, most adult neural stem cells (NSCs) are located in the ventricular–subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior–ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process

Die NO-sensitiven Guanylyl Cyclase Isoformen und ihre Bedeutung für die synaptische Plastizität im Hippocampus der Maus

Stickstoffmonoxid (NO) ist ein wichtiges Signalmolekül, welches im Gehirn als Neurotransmitter fungiert und hierdurch die synaptische Aktivität entscheidend moduliert. NO bindet vorrangig an die NO-sensitive Guanylyl Zyklase (NO-GC), was zur cGMP Bildung führt. NO-GC kommt in zwei Isoformen, der NO-GC1 und NO-GC2 vor. Mittels zweier Knock-out Mausmodelle, bei denen jeweils eine NO-GC Isoform genetisch inaktiv ist, wurde die physiologische Rolle beider NO-GCs an der exzitatorischen Signalübertragung in der CA1 Region des Hippocampus untersucht. Hierbei wurden zwei verschiedene NO/cGMP-Signalwege an CA3-CA1 Synapsen detektiert. Der präsynaptische NO/cGMP-Signalweg erfolgt durch die Aktivierung von eNOS und NO-GC1 und beeinflusst die Glutamatfreisetzung, während in der postsynaptischen Seite NO von nNOS gebildet wird und mittels NO-GC2 einen Einfluss auf die Aktivierung der NMDA-Rezeptoren ausübt. Weiterhin konnte die Beteiligung der HCN-Kanäle als cGMP-Effektoren nachgewiesen werden

Focal cortical lesions induce bidirectional changes in the excitability of fast spiking and non fast spiking cortical interneurons.

A physiological brain function requires neuronal networks to operate within a well-defined range of activity. Indeed, alterations in neuronal excitability have been associated with several pathological conditions, ranging from epilepsy to neuropsychiatric disorders. Changes in inhibitory transmission are known to play a key role in the development of hyperexcitability. However it is largely unknown whether specific interneuronal subpopulations contribute differentially to such pathological condition. In the present study we investigated functional alterations of inhibitory interneurons embedded in a hyperexcitable cortical circuit at the border of chronically induced focal lesions in mouse visual cortex. Interestingly, we found opposite alterations in the excitability of non fast-spiking (Non Fs) and fast-spiking (Fs) interneurons in acute cortical slices from injured animals. Non Fs interneurons displayed a depolarized membrane potential and a higher frequency of spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, Fs interneurons showed a reduced sEPSCs amplitude. The observed downscaling of excitatory synapses targeting Fs interneurons may prevent the recruitment of this specific population of interneurons to the hyperexcitable network. This mechanism is likely to seriously affect neuronal network function and to exacerbate hyperexcitability but it may be important to protect this particular vulnerable population of GABAegic neurons from excitotoxicity

Physiological Properties of Supragranular Cortical Inhibitory Interneurons Expressing Retrograde Persistent Firing

Neurons are polarized functional units. The somatodendritic compartment receives and integrates synaptic inputs while the axon relays relevant synaptic information in form of action potentials (APs) across long distance. Despite this well accepted notion, recent research has shown that, under certain circumstances, the axon can also generate APs independent of synaptic inputs at axonal sites distal from the soma. These ectopic APs travel both toward synaptic terminals and antidromically toward the soma. This unusual form of neuronal communication seems to preferentially occur in cortical inhibitory interneurons following a period of intense neuronal activity and might have profound implications for neuronal information processing. Here we show that trains of ectopically generated APs can be induced in a large portion of neocortical layer 2/3 GABAergic interneurons following a somatic depolarization inducing hundreds of APs. Sparsely occurring ectopic spikes were also observed in a large portion of layer 1 interneurons even in absence of prior somatic depolarization. Remarkably, we found that interneurons which produce ectopic APs display specific membrane and morphological properties significantly different from the remaining GABAergic cells and may therefore represent a functionally unique interneuronal subpopulation

Physiological properties of supragranular cortical inhibitory interneurons expressing retrograde persistent firing

Neurons are polarized functional units. The somatodendritic compartment receives and integrates synaptic inputs while the axon relays relevant synaptic information in form of action potentials (APs) across long distance. Despite this well accepted notion, recent research has shown that, under certain circumstances, the axon can also generate APs independent of synaptic inputs at axonal sites distal from the soma. These ectopic APs travel both toward synaptic terminals and antidromically toward the soma. This unusual form of neuronal communication seems to preferentially occur in cortical inhibitory interneurons following a period of intense neuronal activity and might have profound implications for neuronal information processing. Here we show that trains of ectopically generated APs can be induced in a large portion of neocortical layer 2/3 GABAergic interneurons following a somatic depolarization inducing hundreds of APs. Sparsely occurring ectopic spikes were also observed in a large portion of layer 1 interneurons even in absence of prior somatic depolarization. Remarkably, we found that interneurons which produce ectopic APs display specific membrane and morphological properties significantly different from the remaining GABAergic cells and may therefore represent a functionally unique interneuronal subpopulation

Changes in excitatory synaptic inputs onto Fs and Non Fs interneurons.

<p><b>A)</b> Representative EPSCs recorded at −60 mV evoked by pairs of synaptic stimulations with an interstimulus interval (ISI) of 30 ms recorded from two Non Fs interneurons (in sham-operated and lesion animals). <b>B)</b> Summary diagram of the mean paired-pulse ratio (PPR) for different ISIs. <b>C)</b> Plot showing sEPSCs frequency versus resting membrane potential (Vm) in Non Fs interneurons showing no correlations between the two parameters. <b>D)</b> Excitatory current amplitude per second (ECA/s) experience by a theoretical population of Fs and Non Fs interneurons.</p

Lesion-induced changes in spontaneous excitatory synaptic inputs onto interneurons.

<p><b>A)</b> Representative sEPSCs traces recorded at −60 mV in Fs (left) and Non Fs (right) layers 2/3 interneurons. The application of DNQX (20 µM) abolished all signals confirming that they were due to the activation of AMPA receptors. <b>B)</b> Plot showing sEPSCs frequency versus sEPSCs amplitude in each recorded neuron. <b>C)</b> Mean sEPSCs frequency and amplitude in each experimental group. <b>D)</b> Plot showing sEPSCs decay time versus sEPSCs rise time in each recorded neuron. <b>E)</b> Mean sEPSCs decay and rise time in each experimental group.</p

Characterization of fast spiking (Fs) and Non fast spiking (Non Fs) interneurons.

<p><b>A)</b> Voltage traces in response to 1 sec-lasting, supra-threshold somatic current injection (100 pA) in a representative Fs (top) and Non Fs (bottom) interneuron. The inset on the right emphasizes the different action potential waveform in the two cell types. <b>B)</b> Plot displaying the coefficient of adaptation versus the spike half-width in each recorded cell. Note the presence of two non overlapping clusters of neurons separated by the dashed line. <b>C)</b> Mean coefficient of adaptiation and spike half-width in each experimental group. <b>D)</b> Triple immunofluorescence stainings for biocytin (red), GFP (green) and Parvalbumin (blue) in one representative Fs (top) and two Non Fs (bottom) neurons.</p