Medium spiny neurons (MSNsϩ MSNs may be a potential target for therapeutic intervention.
Neuregulin 1 (NRG-1) and its receptor ErbB4 have emerged as biologically plausible schizophrenia risk factors, modulators of GABAergic and dopaminergic neurotransmission, and as potent regulators of glutamatergic synaptic plasticity. NRG-1 acutely depotentiates LTP in hippocampal slices, and blocking ErbB kinase activity inhibits LTP reversal by theta pulse stimuli (TPS), an activity-dependent reversal paradigm. NRG-1/ErbB4 signaling in parvalbumin (PV) interneurons has been implicated in inhibitory transmission onto pyramidal neurons. However, the role of ErbB4, in particular in PV interneurons, for LTP reversal has not been investigated. Here we show that ErbB4 null (ErbB4-/-) and PV interneuron-restricted mutant (PV-Cre;ErbB4) mice, as well as NRG-1 hypomorphic mice, exhibit increased hippocampal LTP. Moreover, both ErbB4-/- and PV-Cre;ErbB4 mice lack TPS-mediated LTP reversal. A comparative behavioral analysis of full and conditional ErbB4 mutant mice revealed that both exhibit hyperactivity in a novel environment and deficits in pre-pulse inhibition of the startle response. Strikingly, however, only ErbB4-/- mice exhibit reduced anxiety-like behaviors in the elevated plus maze task and deficits in cued and contextual fear conditioning. These results suggest that aberrant NRG-1/ErbB4 signaling in PV interneurons accounts for some but not all behavioral abnormalities observed in ErbB4-/- mice. Consistent with the observation that PV-Cre;ErbB4 mice exhibit normal fear conditioning, we find that ErbB4 is broadly expressed in the amygdala, largely by cells negative for PV. These findings are important to better understand ErbB4's role in complex behaviors and warrant further analysis of ErbB4 mutant mice lacking the receptor in distinct neuron types.
Objective Drug exposure during critical periods of brain development may adversely affect nervous system function, posing a challenge for treating of infants. This is of particular concern for treating neonatal seizures, as early-life exposure to drugs such as phenobarbital is associated with adverse neurological outcomes in patients and induction of neuronal apoptosis in animal models. The functional significance of the preclinical neurotoxicity has been questioned due to the absence of evidence for functional impairment associated with drug-induced developmental apoptosis. Method We used patch-clamp recordings to examine functional synaptic maturation in striatal medium spiny neurons (MSNs) from neonatal rats exposed to antiepileptic drugs with proapoptotic action (phenobarbital, phenytoin, lamotrigine) and without proapoptotic action (levetiracetam). Phenobarbital-exposed rats were also assessed for reversal learning at weaning. Result Recordings from control animals revealed increased inhibitory and excitatory synaptic connectivity between postnatal day (P)10 and 18. This maturation was absent in rats exposed at P7 to a single dose of phenobarbital, phenytoin, or lamotrigine. Additionally, phenobarbital exposure impaired striatal-mediated behavior on P25. Neuroprotective pretreatment with melatonin, which prevents drug-induced neurodevelopmental apoptosis, prevented the drug-induced disruption in maturation. Levetiracetam was found not to disrupt synaptic development. Interpretation Our results provide the first evidence that exposure to antiepileptic drugs during a sensitive postnatal period impairs physiological maturation of synapses in neurons that survive the initial drug insult. These findings suggest a mechanism by which early-life exposure to AEDs can impact cognitive and behavioral outcomes, underscoring the need to identify therapies that control seizures without compromising synaptic maturation.
We previously reported greater GABA A receptor-mediated tonic currents in D 2 ϩ striatopallidal than D 1 ϩ striatonigral medium spiny neurons (MSNs) are mediated by ␣5-subunit-containing receptors. Here, we used whole-cell recordings in slices from bacterial artificial chromosome transgenic mice to investigate the link between subunit composition, phosphorylation, and dopamine receptor activation. Whole-cell recordings in slices from ␦-subunit knock-out mice demonstrate that while MSNs in wild-type mice do express ␦-subunitcontaining receptors, this receptor subtype is not responsible for tonic conductance observed in the acute slice preparation. We assessed the contribution of the 1-and 3-subunits expressed in MSNs by their sensitivity to etomidate, an agonist selective for 2-or 3-subunit-containing GABA A receptors. Although etomidate produced substantial tonic current in D 2 ϩ neurons, there was no effect in D 1 ϩ neurons. However, with internal PKA application or dopamine modulation, D 1 ϩ neurons expressed tonic conductance and responded to etomidate application. Our results suggest that distinct phosphorylation of 3-subunits may cause larger tonic current in D 2 ϩ striatopallidal MSNs, and proper intracellular conditions can reveal tonic current in D 1 ϩ cells.
Key points• Pharmacological activation of nicotinic ACh receptors (nAChRs) excites striatal interneurones and induces a GABA-mediated current in medium spiny projecting neurones (MSNs) via feedforward inhibition. Abstract Choline acetyltransferase-expressing interneurones (ChAT)+ of the striatum influence the activity of medium spiny projecting neurones (MSNs) and striatal output via a disynaptic mechanism that involves GABAergic neurotransmission. Using transgenic mice that allow visual identification of MSNs and distinct populations of GABAergic interneurones expressing neuropeptide Y (NPY) + , parvalbumin (PV) + and tyrosine hydroxylase (TH) + , we further elucidate this mechanism by studying nicotinic ACh receptor (nAChR)-mediated responses. First, we determined whether striatal neurones exhibit pharmacologically induced nicotinic responses by performing patch-clamp recordings. With high [Cl − ] i , our results showed increased spontaneous IPSC frequency and amplitude in MSNs as well as in the majority of interneurones. However, direct nAChR-mediated activity was observed in interneurones but not MSNs. In recordings with physiological [Cl − ] i , these responses manifested as inward currents in the presence of tetrodotoxin and bicuculline methobromide. Nicotinic responses in MSNs were primarily mediated through GABA A receptors in feedforward inhibition. To identify the GABAergic interneurones that mediate the response, we performed dual recordings from GABAergic interneurones and MSNs. Both TH + and neurogliaform subtypes of NPY + (NPY + NGF) interneurones form synaptic connections with MSNs, although the strength of connectivity, response kinetics and pharmacology differ between and within the two populations. Importantly, both cell types appear to contribute to nAChR-mediated GABAergic responses in MSNs. Our data offer insight into the striatal network activity under cholinergic control, and suggest that subclasses of recently identified TH + and R. Luo and M. J. Janssen have contributed equally to this work.
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