The GABAB1b Isoform Mediates Long-Lasting Inhibition of Dendritic Ca2+ Spikes in Layer 5 Somatosensory Pyramidal Neurons

Abstract

The apical tuft of layer 5 pyramidal neurons is innervated by a large number of inhibitory inputs with unknown functions. Here, we studied the functional consequences and underlying molecular mechanisms of apical inhibition on dendritic spike activity. Extracellular stimulation of layer 1, during blockade of glutamatergic transmission, inhibited the dendritic Ca2+ spike for up to 400 ms. Activation of metabotropic GABAB receptors was responsible for a gradual and long-lasting inhibitory effect, whereas GABAA receptors mediated a short-lasting (approximately 150 ms) inhibition. Our results suggest that the mechanism underlying the GABAB inhibition of Ca2+ spikes involves direct blockade of dendritic Ca2+ channels. By using knockout mice for the two predominant GABAB1 isoforms, GABAB1a and GABAB1b, we showed that postsynaptic inhibition of Ca2+ spikes is mediated by GABAB1b, whereas presynaptic inhibition of GABA release is mediated by GABAB1a. We conclude that the molecular subtypes of GABAB receptors play strategically different physiological roles in neocortical neurons.

The response of cortical neurons to in vivo-like input current: theory and experiment: II. Time-varying and spatially distributed inputs

“…This phenomenon relies on regenerative dendritic calcium conductances and can be tuned by acting directly on those conductances (Larkum et al 2004), e.g. by selectively blocking them through activation of dendritic GABA A and GABA B receptors (Pérez-Garci et al 2006). These tuning options extend the functionality of pyramidal neurons by allowing them to distinguish between synaptic drivers, modulators and disruptors (see Sherman and Guillery 1998 and Fig.…”

“…Inhibition may shunt the somatic voltage when the excitatory synaptic input projects proximally to the soma (Doiron et al 2001;Mitchell and Silver 2003), or it may transiently block the calcium conductance and thus disrupt the gain modulation due to calcium spikes when the excitatory synaptic input projects to the distal dendrite (Larkum et al 1999;Pérez-Garci et al 2006). …”

Imaging synaptic inhibition in transgenic mice expressing the chloride indicator, Clomeleon

“…Membrane potential recordings were corrected for the liquid junction potential (14 mV). Parameters for wild type tissue were taken from (Pérez-Garci et al, 2006) and (Agmon and Connors, 1992).…”

Numerical modelling of plasticity induced by transcranial magnetic stimulation

“…This function incorporates the timecourse of the excitatory post-synaptic potential (EPSP). However, for the case of inhibitory synapses (b = i) we include the effects of both GABA A and the much longer lasting (several hundred milliseconds [32,34]) GABA B neurostransmitters. Therefore we use a combination of two of these functions for the inhibitory postsynaptic potential (IPSP):…”

“…Table 1 gives a list of standard parameters chosen for this modelling. Values for the mean-field cortical modelling have been chosen drawing from references [38,39,37,11,45,46], with smaller rates being used for α B and β B to model the long timescale GABA B inhibitory post-synaptic potentials [32,34]. Values for the STDP have been chosen with reference to [1] and [11].…”