GABAB receptors in maintenance of neocortical circuit function

Abstract

Activation of metabotropic GABAB receptors (GABABRs), which enhances tonic GABA current, substantially increases the frequency of spontaneous seizures. Despite these pro-epileptic consequences of GABABR activation, mice lacking functional GABAB receptors (GABAB1R KO mice) exhibit clonic and rare absence seizures. To examine these mice further, we recorded excitatory and inhibitory synaptic inputs and tonic GABA currents from Layer 2 neocortical pyramidal neurons of GABAB1R WT and KO mice (P30-40). Tonic current was increased while the frequency of synaptic inputs was unchanged in KO mice relative to WT littermates. The neocortical laminar distribution of interneuron subtypes derived from the medial ganglionic eminence (MGE) was also not statistically different in KO mice relative to WT while the number of calretinin-positive, caudal GEderived, cells in Layer 1 was reduced. Transplantation of MGE progenitors obtained from KO mice lacking functional GABAB1R did not increase tonic inhibition in the host brain above that of media-injected controls. Taken together, these results suggest a complex role for GABAB receptors in mediating neocortical circuit function.

Medial Ganglionic Eminence Progenitors Transplanted into Hippocampus Integrate in a Functional and Subtype-Appropriate Manner

“…1 D ). These results using ChR2 mouse donor embryos are consistent with previous studies (Alvarez-Dolado et al, 2006; Baraban et al, 2009; Southwell et al, 2012; Hunt et al, 2013; Howard et al, 2014; Sebe et al, 2014a, 2014b; Hunt and Baraban, 2015; Howard and Baraban, 2016)…”

“…1 D , E ; Alvarez-Dolado et al, 2006; Hunt et al, 2013; Howard et al, 2014; Sebe et al, 2014b; Zhou et al, 2015), it is not yet settled whether they also have proper synaptic characteristics matching their interneuron subtypes. Comprehensive recapitulation of functional features is essential to any type of cell-based therapy.…”

Interneuron Transplantation as a Treatment for Epilepsy

“…In regions of the host brain containing MGE-grafted interneurons, both synaptic ( phasic) and extrasynaptic (tonic) inhibition is enhanced in nearby pyramidal neurons, but not in host interneurons. However, increases in tonic inhibition were only observed when extrasynaptic currents were pharmacologically isolated, not under physiological recording conditions (Baraban et al 2009;Sebe et al 2014b). Collectively, these findings suggest that, similar to endogenously born MGE subtypes, grafted MGE cells maintain their natural propensity for targeting glutamatergic principal neurons.…”

Effects of GABAB receptor positive allosteric modulator BHF177 and IRS‐1 on apoptosis of hippocampal neurons in rats with refractory epilepsy via the PI3K/Akt pathway

“…The γ-Aminobutyric acid B (GABA B ) receptor is a G proteincoupled receptor for the inhibitory neurotransmitter GABA, activation of which evokes ionic currents that increase the risk for spontaneous seizures (Geis et al, 2019;Sebe et al, 2014).…”

“…The γ‐Aminobutyric acid B (GABA B ) receptor is a G protein‐coupled receptor for the inhibitory neurotransmitter GABA, activation of which evokes ionic currents that increase the risk for spontaneous seizures (Geis et al, 2019; Sebe et al, 2014). Accumulating evidence indicates that the GABA B receptors are involved in antiepileptic effects (Schuler et al, 2001; Zapata et al, 2017).…”